1,4-Disubstituted benzo-fused urea compounds

ABSTRACT

Disclosed are compounds of the formulas (I) &amp; (II) shown below which are active as anti-inflammatory agents. Also disclosed are methods of using and making such compounds.                    
     wherein G, X, A and Q are described herein.

APPLICATION DATA

This application claims benefit to U.S. provisional application Ser. No.60/330,254 filed Oct. 18, 2001.

TECHNICAL FIELD OF THE INVENTION

This invention relates to 1,4-disubstituted benzo-fused urea compoundsof formulas (I) & (II):

wherein G, X, A and Q of formulas (I)/(II) are defined below. Thecompounds of the invention inhibit production of cytokines involved ininflammatory processes and are thus useful for treating diseases andpathological conditions involving inflammation such as chronicinflammatory disease. This invention also relates to processes forpreparing these compounds and to pharmaceutical compositions comprisingthese compounds.

BACKGROUND OF THE INVENTION

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are importantbiological entities collectively referred to as proinflammatorycytokines. These, along with several other related molecules, mediatethe inflammatory response associated with the immunological recognitionof infectious agents. The inflammatory response plays an important rolein limiting and controlling pathogenic infections.

Elevated levels of proinflammatory cytokines are also associated with anumber of diseases of autoimmunity such as toxic shock syndrome,rheumatoid arthritis, osteoarthritis, diabetes and inflammatory boweldisease (Dinarello, C. A., et al., 1984, Rev. Infect. Disease 6:51). Inthese diseases, chronic elevation of inflammation exacerbates or causesmuch of the pathophysiology observed. For example, rheumatoid synovialtissue becomes invaded with inflammatory cells that result indestruction to cartilage and bone (Koch, A. E., et al., 1995, J. Invest.Med. 43: 28-38). Studies suggest that inflammatory changes mediated bycytokines may be involved in the pathogenesis of restenosis afterpercutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., etal., 2001 March, Coron. Artery Dis. 12(2): 107-13). An important andaccepted therapeutic approach for potential drug intervention in thesediseases is the reduction of proinflammatory cytokines such as TNF (alsoreferred to in its secreted cell-free form as TNFα) and IL-1β. A numberof anti-cytokine therapies are currently in clinical trials. Efficacyhas been demonstrated with a monoclonal antibody directed against TNFαin a number of autoimmune diseases (Heath, P., “CDP571: An EngineeredHuman IgG4 Anti-TNFα Antibody” IBC Meeting on Cytokine Antagonists,Philadelphia, Pa., Apr. 24-5, 1997). These include the treatment ofrheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, E.C. C., et al., 1997, British J. Rheum. 35: 334-342 and Stack, W. A., etal., 1997, Lancet 349: 521-524). The monoclonal antibody is thought tofunction by binding to both soluble TNFα and to membrane bound TNF.

A soluble TNFα receptor has been engineered that interacts with TNFα.The approach is similar to that described above for the monoclonalantibodies directed against TNFα; both agents bind to soluble TNFα, thusreducing its concentration. One version of this construct, called Enbrel(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase IIIclinical trial for the treatment of rheumatoid arthritis (Brower et al.,1997, Nature Biotechnology 15: 1240). Another version of the TNFαreceptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) hasdemonstrated efficacy in various animal models of allergic lunginflammation and acute lung injury. Ro 45-2081 is a recombinant chimericmolecule constructed from the soluble 55 kDa human TNF receptor fused tothe hinge region of the heavy chain IgG1 gene and expressed ineukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143).

IL-1 has been implicated as an immunological effector molecule in alarge number of disease processes. IL-1 receptor antagonist (IL-1ra) hadbeen examined in human clinical trials. Efficacy has been demonstratedfor the treatment of rheumatoid arthritis (Antril, Amgen). In a phaseIII human clinical trial IL-1ra reduced the mortality rate in patientswith septic shock syndrome (Dinarello, 1995, Nutrition 11, 492).Osteoarthritis is a slow progressive disease characterized bydestruction of the articular cartilage. IL-1 is detected in synovialfluid and in the cartilage matrix of osteoarthritic joints. Antagonistsof IL-1 have been shown to diminish the degradation of cartilage matrixcomponents in a variety of experimental models of arthritis (Chevalier,1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator ofcardiovascular homeostasis, neurotransmission and immune function;recently it has been shown to have important effects in the modulationof bone remodeling. Cytokines such as IL-1 and TNF are potentstimulators of NO production. NO is an important regulatory molecule inbone with effects on cells of the osteoblast and osteoclast lineage(Evans, et al., 1996, J Bone Miner. Res. 11, 300). The promotion ofbeta-cell destruction leading to insulin dependent diabetes mellitusshows dependence on IL-1. Some of this damage may be mediated throughother effectors such as prostaglandins and thromboxanes. IL-1 can effectthis process by controlling the level of both cyclooxygenase II andinducible nitric oxide synthetase expression (McDaniel et al., 1996,Proc. Soc. Exp. Biol. Med. 211, 24).

Inhibitors of cytokine production are expected to block induciblecyclooxygenase (COX-2) expression. COX-2 expression has been shown to beincreased by cytokines and it is believed to be the isoform ofcyclooxygenase responsible for inflammation (M. K. O'Banion et al.,Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.) Accordingly, inhibitorsof cytokines such as IL-1 would be expected to exhibit efficacy againstthose disorders currently treated with COX inhibitors such as thefamiliar NSAIDs. These disorders include acute and chronic pain as wellas symptoms of inflammation and cardiovascular disease.

Elevation of several cytokines have been demonstrated during activeinflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1and IL-1ra is present in patients with IBD. Insufficient production ofendogenous IL-1ra may contribute to the pathogenesis of IBD (Cominelli,et al., 1996, Aliment. Pharmacol. Ther. 10, 49). Alzheimer disease ischaracterized by the presence of beta-amyloid protein deposits,neurofibrillary tangles and cholinergic dysfunction throughout thehippocampal region. The structural and metabolic damage found inAlzheimer disease is possibly due to a sustained elevation of IL-1(Holden, et al., 1995, Med. Hypotheses, 45, 559). A role for IL-1 in thepathogenesis of human immunodeficiency virus (HIV) has been identified.IL-1ra showed a clear relationship to acute inflammatory events as wellas to the different disease stages in the pathophysiology of HIVinfection (Kreuzer, et al., 1997, Clin. Exp. Immunol. 109, 54). IL-1 andTNF are both involved in periodontal disease. The destructive processassociated with periodontal disease may be due to a disregulation ofboth IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).

Proinflammatory cytokines such as TNFα and IL-1β are also importantmediators of septic shock and associated cardiopulmonary dysfunction,acute respiratory distress syndrome (ARDS) and multiple organ failure.In a study of patients presenting at a hospital with sepsis, acorrelation was found between TNFα and IL-6 levels and septiccomplications (Terregino et al., 2000, Ann. Emerg. Med. 35, 26). TNFαhas also been implicated in cachexia and muscle degradation, associatedwith HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289).Obesity is associated with an increase incidence of infection, diabetesand cardiovascular disease. Abnormalities in TNFα expression have beennoted for each of the above conditions (Loffreda, et al., 1998, FASEB J.12, 57). It has been proposed that elevated levels of TNFα are involvedin other eating related disorders such as anorexia and bulimia nervosa.Pathophysiological parallels are drawn between anorexia nervosa andcancer cachexia (Holden, et al., 1996, Med. Hypotheses 47, 423). Aninhibitor of TNFα production, HU-211, was shown to improve the outcomeof closed brain injury in an experimental model (Shohami, et al., 1997,J. Neuroimmunol. 72, 169). Atherosclerosis is known to have aninflammatory component and cytokines such as IL-1 and TNF have beensuggested to promote the disease. In an animal model an IL-1 receptorantagonist was shown to inhibit fatty streak formation (Elhage et al.,1998, Circulation, 97, 242).

TNFα levels are elevated in airways of patients with chronic obstructivepulmonary disease and it may contribute to the pathogenesis of thisdisease (M. A. Higham et al., 2000, Eur. Respiratory J., 15, 281).Circulating TNFα may also contribute to weight loss associated with thisdisease (N. Takabatake et al., 2000, Amer. J. Resp. & Crit. Care Med.,161 (4 Pt 1), 1179). Elevated TNFα levels have also been found to beassociated with congestive heart failure and the level has beencorrelated with severity of the disease (A. M. Feldman et al., 2000, J.Amer. College of Cardiology, 35, 537). In addition, TNFα has beenimplicated in reperfusion injury in lung (Borjesson et al., 2000, Amer.J. Physiol., 278, L3-12), kidney (Lemay et al., 2000, Transplantation,69, 959), and the nervous system (Mitsui et al., 1999, Brain Res., 844,192).

TNFα is also a potent osteoclastogenic agent and is involved in boneresorption and diseases involving bone resorption (Abu-Amer et al.,2000, J. Biol. Chem., 275, 27307). It has also been found highlyexpressed in chondrocytes of patients with traumatic arthritis(Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNFα hasalso been shown to play a key role in the development ofglomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78,1625).

The abnormal expression of inducible nitric oxide synthetase (iNOS) hasbeen associated with hypertension in the spontaneously hypertensive rat(Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in theexpression of iNOS and therefore may also have a role in thepathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension,9, 867).

IL-1 has also been shown to induce uveitis in rats which could beinhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol.and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have beenshown to stimulate proliferation of acute myelogenous leukemia blasts(Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essentialfor the development of both irritant and allergic contact dermatitis.Epicutaneous sensitization can be prevented by the administration of ananti-IL-1 monoclonal antibody before epicutaneous application of anallergen (Muller, et al., 1996, Am. J. Contact Dermat. 7, 177). Dataobtained from IL-1 knock out mice indicates the critical involvement infever for this cytokine (Kluger et al., 1998, Clin. Exp. Pharmacol.Physiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 andIL-8 initiate the acute-phase reaction which is stereotyped in fever,malaise, myalgia, headaches, cellular hypermetabolism and multipleendocrine and enzyme responses (Beisel, 1995, Am. J. Clin. Nutr. 62,813). The production of these inflammatory cytokines rapidly followstrauma or pathogenic organism invasion.

Other proinflammatory cytokines have been correlated with a variety ofdisease states. IL-8 correlates with influx of neutrophils into sites ofinflammation or injury. Blocking antibodies against IL-8 havedemonstrated a role for IL-8 in the neutrophil associated tissue injuryin acute inflammation (Harada et al., 1996, Molecular Medicine Today 2,482). Therefore, an inhibitor of IL-8 production may be useful in thetreatment of diseases mediated predominantly by neutrophils such asstroke and myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, hemodialysis, leukopherisis,granulocyte transfusion associated syndromes, and necrotizingenterocolitis.

Rhinovirus triggers the production of various proinflammatory cytokines,predominantly IL-8, which results in symptomatic illnesses such as acuterhinitis (Winther et al., 1998, Am. J. Rhinol. 12, 17).

Other diseases that are effected by IL-8 include myocardial ischemia andreperfusion, inflammatory bowel disease and many others.

The proinflammatory cytokine IL-6 has been implicated with the acutephase response. IL-6 is a growth factor in a number in oncologicaldiseases including multiple myeloma and related plasma cell dyscrasias(Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has alsobeen shown to be an important mediator of inflammation within thecentral nervous system. Elevated levels of IL-6 are found in severalneurological disorders including AIDS dementia complex, Alzheimer'sdisease, multiple sclerosis, systemic lupus erythematosus, CNS traumaand viral and bacterial meningitis (Gruol, et al., 1997, MolecularNeurobiology 15: 307). IL-6 also plays a significant role inosteoporosis. In murine models it has been shown to effect boneresorption and to induce osteoclast activity (Ershler et al., 1997,Development and Comparative Immunol. 21: 487). Marked cytokinedifferences, such as IL-6 levels, exist in vivo between osteoclasts ofnormal bone and bone from patients with Paget's disease (Mills, et al.,1997, Calcif. Tissue Int. 61, 16). A number of cytokines have been shownto be involved in cancer cachexia. The severity of key parameters ofcachexia can be reduced by treatment with anti IL-6 antibodies or withIL-6 receptor antagonists (Strassmann, et al., 1995, Cytokines Mol.Ther. 1, 107). Several infectious diseases, such as influenza, indicateIL-6 and IFN alpha as key factors in both symptom formation and in hostdefense (Hayden, et al., 1998, J. Clin. Invest. 101, 643).Overexpression of IL-6 has been implicated in the pathology of a numberof diseases including multiple mycloma, rheumatoid arthritis,Castleman's disease, psoriasis and post-menopausal osteoporosis(Simpson, et al., 1997, Protein Sci. 6, 929). Compounds that interferedwith the production of cytokines including IL-6, and TNF were effectivein blocking a passive cutaneous anaphylaxis in mice (Scholz et al.,1998, J. Med. Chem., 41, 1050).

GM-CSF is another proinflammatory cytokine with relevance to a number oftherapeutic diseases. It influences not only proliferation anddifferentiation of stem cells but also regulates several other cellsinvolved in acute and chronic inflammation. Treatment with GM-CSF hasbeen attempted in a number of disease states including burn-woundhealing, skin-graft resolution as well as cytostatic and radiotherapyinduced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF alsoappears to play a role in the replication of human immunodeficiencyvirus (HIV) in cells of macrophage lineage with relevance to AIDStherapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41).Bronchial asthma is characterised by an inflammatory process in lungs.Involved cytokines include GM-CSF amongst others (Lee, 1998, J. R. Coll.Physicians Lond 32, 56).

Interferon γ (IFN γ) has been implicated in a number of diseases. It hasbeen associated with increased collagen deposition that is a centralhistopathological feature of graft-versus-host disease (Parkman, 1998,Curr. Opin. Hematol. 5, 22). Following kidney transplantation, a patientwas diagnosed with acute myelogenous leukemia. Retrospective analysis ofperipheral blood cytokines revealed elevated levels of GM-CSF and IFN γ.These elevated levels coincided with a rise in peripheral blood whitecell count (Burke, et al., 1995, Leuk. Lymphoma. 19, 173). Thedevelopment of insulin-dependent diabetes (Type 1) can be correlatedwith the accumulation in pancreatic islet cells of T-cells producing IFNγ (Ablumunits, et al., 1998, J. Autoimmun. 11, 73). IFN γ along withTNF, IL-2 and IL-6 lead to the activation of most peripheral T-cellsprior to the development of lesions in the central nervous system fordiseases such as multiple sclerosis (MS) and AIDS dementia complex(Martino et al., 1998, Ann. Neurol. 43, 340). Atherosclerotic lesionsresult in arterial disease that can lead to cardiac and cerebralinfarction. Many activated immune cells are present in these lesions,mainly T-cells and macrophages. These cells produce large amounts ofproinflammatory cytokines such as TNF, IL-1 and IFN γ. These cytokinesare thought to be involved in promoting apoptosis or programmed celldeath of the surrounding vascular smooth muscle cells resulting in theatherosclerotic lesions (Geng, 1997, Heart Vessels Suppl. 12, 76).Allergic subjects produce mRNA specific for IFN γ following challengewith Vespula venom (Bonay, et al., 1997, Clin. Exp. Immunol. 109, 342).The expression of a number of cytokines, including IFN γ has been shownto increase following a delayed type hypersensitivity reaction thusindicating a role for IFN γ in atopic dermatitis (Szepietowski, et al.,1997, Br. J. Dermatol. 137, 195). Histopathologic and immunohistologicstudies were performed in cases of fatal cerebral malaria. Evidence forelevated IFN γ amongst other cytokines was observed indicating a role inthis disease (Udomsangpetch et al., 1997, Am. J. Trop. Med. Hyg. 57,501). The importance of free radical species in the pathogenesis ofvarious infectious diseases has been established. The nitric oxidesynthesis pathway is activated in response to infection with certainviruses via the induction of proinflammatory cytokines such as IFN γ(Akaike, et al., 1998, Proc. Soc. Exp. Biol. Med. 217, 64). Patients,chronically infected with hepatitis B virus (HBV) can develop cirrhosisand hepatocellular carcinoma. Viral gene expression and replication inHBV transgenic mice can be suppressed by a post-transcriptionalmechanism mediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995,Springer Semin. Immunopathol. 17, 261). IFN γ can selectively inhibitcytokine induced bone resorption. It appears to do this via theintermediacy of nitric oxide (NO) which is an important regulatorymolecule in bone remodeling. NO may be involved as a mediator of bonedisease for such diseases as: the rheumatoid arthritis, tumor associatedosteolysis and postmenopausal osteoporosis (Evans, et al., 1996, J.+Bone Miner Res. 11, 300). Studies with gene deficient mice havedemonstrated that the IL-12 dependent production of IFN γ is critical inthe control of early parasitic growth. Although this process isindependent of nitric oxide the control of chronic infection does appearto be NO dependent (Alexander et al., 1997, Philos Trans R Soc Lond BBiol Sci 352, 1355). NO is an important vasodilator and convincingevidence exists for its role in cardiovascular shock (Kilbourn, et al.,1997, Dis Mon. 43, 277). IFN γ is required for progression of chronicintestinal inflammation in such diseases as Crohn's disease andinflammatory bowel disease (IBD) presumably through the intermediacy ofCD4+ lymphocytes probably of the TH1 phenotype (Sartor 1996, AlimentPharmacol Ther. 10 Suppl 2, 43). An elevated level of serum IgE isassociated with various atopic diseases such as bronchial asthma andatopic dermatitis. The level of IFN γ was negatively correlated withserum IgE suggesting a role for IFN γ in atopic patients (Teramoto etal., 1998, Clin Exp Allergy 28, 74).

WO 01/01986 discloses particular compounds alleged to having the abilityto inhibit TNF-alpha. The specific inhibitors disclosed are structurallydistinct from the novel compounds disclosed in the present applicationdisclosed hereinbelow. Certain compounds disclosed in WO 01/01986 areindicated to be effective in treating the following diseases: dementiaassociated with HIV infection, glaucoma, optic-neuropathy, opticneuritis, retinal ischemia, laser induced optic damage, surgery ortrauma-induced proliferative vitreoretinopathy, cerebral ischemia,hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbonmonoxide or manganese or cyanide poisoning, Huntington's disease,Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosisand other demyelinating diseases, amyotrophic lateral sclerosis, headand spinal cord trauma, seizures, convulsions, olivopontocerebellaratrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-relatedneuropathy, MERRF and MELAS syndromes, Leber's disease, Wernicke'sencephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia,hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyricaminoaciduria, sulfite oxidase deficiency, combined systems disease,lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drugaddiction, drug tolerance, drug dependency, depression, anxiety andschizophrenia. WO 02/32862 discloses that inhibitors of pro-inflammatorycytokines including TNFα are allegedly useful for treating acute andchronic inflammation in the lung caused by inhalation of smoke such ascigarette smoke. TNF anatagonists are apparently also useful for thetreatment of endometriosis, see EP 1022027 A1. Infliximab, in clinicaltrials for RA, has also been indicated to be useful for treating variousinflammatory diseases including Behcet's disease, uveitis and ankylosingspondylitis. Pancreatitis may also be regulated by inflammatory mediatorproduction, see J Surg Res 2000 May 15, 90(2)95-101; Shock 1998 Sep.10(3):160-75. p38MAP kinase pathway plays an role inB.burgdorferi-elicited infammation and may be useful in treatinginflammation induced by the Lyme disease agent. Anguita, J. et. al., TheJournal of Immunology, 2002, 168:6352-6357.

Compounds which modulate release of one or more of the aforementionedinflammatory cytokines can be useful in treating diseases associatedwith release of these cytokines. For example, WO 98/52558 disclosesheteroaryl urea compounds which are indicated to be useful in treatingcytokine mediated diseases. WO 99/23091 discloses another class of ureacompounds which are useful as anti-inflammatory agents. WO 99/32463relates to aryl ureas and their use in treating cytokine diseases andproteolytic enzyme mediated disease. WO 00/41698 discloses aryl ureassaid to be useful in treating p38 MAP kinase diseases.

U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclicsubstituted urea compounds which are described as being useful fortreating hypercholesterolemia and atheroclerosis.

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of various diseasestates. Some protein therapeutics are in late development or have beenapproved for use in particular diseases. Protein therapeutics are costlyto produce and have bioavailability and stability problems. Therefore aneed exists for new small molecule inhibitors of cytokine productionwith optimized efficacy, pharmacokinetic and safety profiles.

All references cited in this application are incorporated herein intheir entirety.

BRIEF SUMMARY OF THE INVENTION

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of various diseasestates.

It is therefore an object of the invention to provide compounds whichinhibit the release of inflammatory cytokines such as interleukin-1 andtumor necrosis factor.

It is a further object of the invention to provide methods for treatingdiseases and pathological conditions involving inflammation such aschronic inflammatory disease, using the novel compounds of theinvention.

It is yet a further object of the invention to provide processes ofpreparation of the above-mentioned novel compounds.

DETAILED DESCRIPTION OF THE INVENTION

In a first broad generic aspect of the invention, there are providedcompounds of the formula (I):

ring A is:

fused saturated or unsaturated ring containing 3-5 carbon atoms whereinring A or the phenyl ring to which it is fused is optionally substitutedby one or more C₁₋₆ branched or unbranched alkyl, acetyl, aroyl, C₁₋₆branched or unbranched alkoxy, halogen, methoxycarbonyl, phenylsulfonyl,hydroxy, amino, mono- or di-(C₁₋₄ alkyl)amino, mono- or di-(C₁₋₄alkyl)amino-S(O)_(m), cyano, nitro or H₂NSO₂;

Preferred formula (I) compounds are those where ring A and the phenylring to which it is fused form:

G is a 5-membered heteroaryl ring;

wherein G is optionally substituted by one or more R₁, R₂ or R₃;

Q is

a carbocyclic ring chosen from naphthyl, benzocyclobutanyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl,benzocycloheptenyl, indanyl and indenyl;

a ring system chosen from benzoxazinyl, benzimidazolyl, benzothiazolyl,benzooxazolyl, benzofuranyl, benzopyranyl, benzodioxolyl, quinaldinyl,quinazolinyl, quinoxalinyl, isoquinolinyl, quinolinyl, indolyl,isoindolyl, indolinyl, purinyl, tetrahydroquinolinyl, indazolyl,imidazo-pyridinyl, pyrazolo-pyridinyl, pyrazolo-pyrimidinyl,pyrrolo-pyrimidinyl, pyrrolo-pyridinyl, pyrido-pyrazinyl,pyrido-pyrimidinyl, pyrido-oxazinyl, pyrido-thiazinyl, pyrido-oxazolyl,pyrido-thioxazolyl, pyrimido-pyrimidine, pteridinyl, cinnolinyl andnaphthyridinyl;

wherein each Q is optionally substituted with one to three Y,

each Y is independently chosen from

L-NR₅R₆ wherein L is a bond, —(CH₂)₁₋₅— or >C(O),

hydrogen, oxo, C₁₋₅ alkyl branched or unbranched, C₁₋₃ alkyl(OH), C₂₋₅alkenyl, C₁₋₃ acyl, heterocyclylC₀₋₃ alkyl wherein the heterocyclyl ischosen from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydropyranyl and tetrahydrofuryl, heteroarylC₀₋₃ alkyl wherein theheteroaryl is chosen from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiofuranyl,quinoxalinyl, quinazolinyl and indazolyl and arylC₀₋₃ alkyl,

wherein each Y is optionally substituted by one to three hydroxy, oxo,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl, C₁₋₅ alkoxycarbonyl, —NR₅R₆ orNR₅R₆—C(O)—;

each R₅ or R₆ is independently:

hydrogen, arylC₀₋₃ alkyl, C₃₋₇ cycloalkylC₀₋₃ alkyl, heterocyclylC₀₋₃alkyl or heterocyclylcarbonyl wherein the heterocyclyl is as hereinabovedescribed for Y, heteroarylC₀₋₃ alkyl or heteroarylcarbonyl wherein theheteroaryl is as hereinabove described for Y, C₁₋₃ acyl, aroyl or C₁₋₆branched or unbranched alkyl, each R₅ or R₆ is optionally substituted byC₁₋₅ alkoxy, hydroxy, mono- or di-C₁₋₃alkylaminocarbonyl, mono or diC₁₋₃alkyl amino, mono or diC₁₋₃ alkylsulfonylamino or C₁₋₃ alkylsulfonyl;

each R₁ is independently:

C₁₋₁₀ alkyl branched or unbranched, wherein one or more C atoms areoptionally independently replaced by O, N or S(O)_(m), and wherein saidC₁₋₁₀ alkyl is optionally substituted with one to three C₃₋₁₀cycloalkyl, hydroxy, oxo, phenyl, naphthyl or halogen;

or R₁ is

cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy orcycloheptyloxy each optionally substituted with one to three C₁₋₃ alkylgroups, nitrile, hydroxyC₁₋₃alkyl or aryl;

phenyloxy or benzyloxy each optionally substituted with one to threeC₁₋₃ alkyl groups, nitrile, hydroxyC₁₋₃alkyl or aryl;

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each beingoptionally substituted with one to three C₁₋₃ alkyl, nitrile,hydroxyC₁₋₃alkyl or aryl;

C₃₋₁₀ branched or unbranced alkenyl each being optionally substitutedwith one to three C₁₋₅ branched or unbranched alkyl, phenyl or naphthyl;

cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein eachoptionally substituted with one to three C₁₋₃ alkyl groups;

oxo, nitrile, halogen; or

C₃₋₆ alkynyl branched or unbranched carbon chain wherein one or moremethylene groups are optionally replaced by O, N or S(O)_(m) and whereinsaid alkynyl group is optionally independently substituted with one totwo oxo groups, hydroxy, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, C₁₋₄alkyl optionally substituted by one or more halogen atoms, nitrile,morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl,tetrazolyl or mono- or di(C₁₋₃alkyl)amino;

each R₂ is independently:

a C₁₋₆ branched or unbranched alkyl optionally halogenated, C₁₋₆acyl,aroyl, C₁₋₄ branched or unbranched alkoxy optionally halogenated,halogen, methoxycarbonyl, C₁₋₄ alkyl-S(O)_(m) branched or unbranched orphenyl-S(O)_(m);

each R₃ is independently C₁₋₆ branched or unbranched alkyl, arylC₀₋₆alkyl, heteroarylC₀₋₆ alkyl or heterocyclyl C₀₋₆ alkyl each optionallysubstituted with one to three C₁₋₃ alkyl groups, nitrile,hydroxyC₁₋₃alkyl or aryl;

each m is independently 0, 1 or 2;

and X is O or S;

or the pharmaceutically acceptable derivatives thereof;

with the proviso that the following compounds are excluded:

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(1-morpholin-4-yl-indan-5-yl)-naphthalen-1-yl]-ureaand

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-benzyl-3H-imidazo[4,5]pyridin-6-yl)naphthalen-1-yl]-urea.

In one embodiment of the invention there are provided compounds of theformula (I) as described in the first generic embodiment immediatelyabove and wherein:

G is pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl oroxazolyl;

wherein G is optionally substituted by one to three R₁, R₂ or R₃;

ring A and the phenyl ring to which it is fused form:

Q is

a ring system chosen from benzimidazolyl, benzothiazolyl, benzooxazolyl,benzisoxazolyl, benzofuranyl, benzodioxolyl, indolyl, isoindolyl,imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, purinyl, indazolyl,quinolinyl, isoquinolinyl, quinazolinyl, benzopyranyl, benzoxazinyl,pyrido[2,3-b]oxazinyl, pyrido[2,3-b]pyrazinyl, pyrido[2,3-b]thiazinyl,pyrrolo[3,2-c]pyridinyl and pyrazolo[3,4-d]pyrimidinyl;

wherein each Q is optionally substituted with one to three Y,

R₁ is

C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy each branched or unbranched and optionallysubstituted with one to three C₃₋₁₀ cycloalkyl, hydroxy, oxo, phenyl,naphthyl or halogen,

or R₁ is

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each optionallysubstituted with one to three C₁₋₃ alkyl, nitrile, hydroxyC₁₋₃alkyl oraryl;

R₃ is C₁₋₆ branched or unbranched alkyl, phenyl, naphthyl, benzyl,phenethyl, heteroarylC₀₋₆ alkyl wherein the heteroaryl is chosen frompyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl,tetrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzopyrazolyl, benzothiofuranyl, quinoxalinyl, quinazolinyl andindazolyl or heterocyclylC₀₋₆ alkyl wherein the heterocyclyl is chosenfrom morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl andtetrahydrofuryl, each optionally substituted with one to three C₁₋₃alkyl; and

X is O.

In another embodiment of the invention there are provided compounds ofthe formula (I) as described in the embodiment immediately above andwherein:

G is pyrrolyl, imidazolyl or pyrazolyl,

wherein G is optionally substituted by one to three R₁, R₂ or R₃;

each Y is independently chosen from

L-NR₅R₆ wherein L is a bond, —(CH₂)₁₋₅— or >C(O),

hydrogen, oxo, C₁₋₅ alkyl branched or unbranched, C₁₋₃ alkyl(OH), C₂₋₅alkenyl, C₁₋₃ acyl, heterocyclylC₀₋₃ alkyl wherein the heterocyclyl ischosen from morpholinyl, piperazinyl, and pyrrolidinyl, heteroarylC₀₋₃alkyl wherein the heteroaryl is chosen from pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl,thiazolyl, and oxazolyl, phenyl, naphthyl, benzyl and phenethyl,

wherein each Y is optionally substituted by one to three hydroxy, oxo,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl, C₁₋₅ alkoxycarbonyl or —NR₅R₆;

each R₅ or R₆ is independently:

hydrogen, phenyl, naphthyl, benzyl, phenethyl, C₃₋₇ cycloalkylC₀₋₃alkyl, heterocyclylC₀₋₃ alkyl or heterocyclylcarbonyl wherein theheterocyclyl is chosen from morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, heteroarylC₀₋₃ alkyl or heteroarylcarbonyl whereinthe heteroaryl is chosen from pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl, C₁₋₃ acyl, aroyl or C₁₋₆ branched or unbranched alkyl, eachR₅ or R₆ is optionally substituted by C₁₋₅ alkoxy, mono or diC₁₋₃ alkylamino, mono or diC₁₋₃ alkylsulfonylamino or C₁₋₃ alkylsulfonyl;

R₁ is

C₁₋₁₀ alkyl, C₁₋₉ alkoxy each branched or unbranched and optionallysubstituted with one to three C₃₋₁₀ cycloalkyl, hydroxy, oxo, phenyl,naphthyl, fluoro, bromo or chloro; and

R₃ is C₁₋₆ branched or unbranched alkyl, phenyl, naphthyl, benzyl,phenethyl, pyridinyl, morpholinyl, piperazinyl, piperidinyl orpyrrolidinyl each optionally substituted with one to three C₁₋₃ alkyl.

In yet another embodiment of the invention there are provided compoundsof the formula (I) as described in the embodiment immediately above andwherein:

G is pyrazolyl optionally substituted by one to three R₁, R₂ or R₃;

Q is chosen from imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,pyrido[2,3-b]oxazinyl and pyrrolo[3,2-c]pyridinyl;

wherein each Q is optionally substituted with one to three Y;

each Y is independently chosen from

L-NR₅R₆ wherein L is a bond, —(CH₂)₁₋₅— or >C(O),

hydrogen, oxo, C₁₋₅ alkyl branched or unbranched, heterocylylC₀₋₃ alkylwherein the heterocyclyl is chosen from morpholinyl, piperazinyl, andpyrrolidinyl, pyridinylC₀₋₃ alkyl or benzyl,

wherein each Y is optionally substituted by one to three hydroxy, oxo,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl or —NR₅R₆; and

each R₅ or R₆ is independently:

hydrogen, phenyl, benzyl, C₃₋₆ cycloalkylC₀₋₃ alkyl, heterocyclylC₀₋₃alkyl or heterocyclylcarbonyl wherein the heterocyclyl is chosen frommorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinylC₀₋₃ alkyl,pyridinylcarbonyl, C₁₋₃ acyl, benzoyl or C₁₋₆ branched or unbranchedalkyl, each R₅ or R₆ is optionally substituted by C₁₋₅ alkoxy, mono ordiC₁₋₃ alkyl amino, mono or diC₁₋₃ alkylsulfonylamino or C₁₋₃alkylsulfonyl.

In still another embodiment of the invention there are providedcompounds of the formula (I) as described in the embodiment immediatelyabove and wherein:

G is 2H-pyrazol-3-yl optionally substituted by one to three R₁, R₂ orR₃;

Q is chosen from:

R₁ is

CF₃, OCF₃, —C(CH₃)₃, —C(CH₂F)₃ or —CH₂C(CH₃)₃; and

R₃ is phenyl or benzyl each optionally substituted with one to threeC₁₋₃ alkyl.

In yet still another embodiment of the invention there are providedcompounds of the formula (I) as described in the embodiment immediatelyabove and wherein:

G is:

Q is chosen from

Y is independently chosen from

L-NR₅R₆ wherein L is a bond or —(CH₂)₁₋₃—,

C₁₋₅ alkyl branched or unbranched, morpholinylC₀₋₃ alkyl or benzyl; and

each R₅ or R₆ is independently:

hydrogen, phenyl, benzyl or C₃₋₆ cycloalkylC₀₋₃ alkyl.

In a second broad generic aspect of the invention, there are providedcompounds of the formula (II):

ring A is:

fused saturated or unsaturated ring containing 3-5 carbon atoms whereinring A or the phenyl ring to which it is fused is optionally substitutedby one or more a C₁₋₆ branched or unbranched alkyl, acetyl, aroyl, C₁₋₆branched or unbranched alkoxy, halogen, methoxycarbonyl, phenylsulfonyl,hydroxy, amino, mono- or di-(C₁₋₄ alkyl)amino, mono- or di-(C₁₋₄alkyl)amino-S(O)_(m), cyano, nitro or H₂NSO₂;

Preferred formula (II) compounds are those where ring A and the phenylring to which it is fused form:

G is

a 6-membered monocyclic heteroaryl ring chosen from pyridinyl,pyrimidinyl, pyrazinyl, and pyridazinyl;

a ring system chosen from benzoxazinyl, benzimidazolyl, benzothiazolyl,benzooxazolyl, benzofuranyl, benzopyranyl, benzodioxolyl, quinaldinyl,quinazolinyl, quinoxalinyl, isoquinolinyl, quinolinyl, indolyl,isoindolyl, indolinyl, purinyl, indazolyl, imidazo-pyridinyl,pyrazolo-pyridinyl, pyrazolo-pyrimidinyl, pyrrolo-pyrimidinyl,pyrrolo-pyridinyl, pyrido-pyrazinyl, pyrido-pyrimidinyl,pyrido-oxazinyl, pyrido-thiazinyl, pyrido-oxazolyl, pyrido-thioxazolyl,pyrimido-pyrimidine, pteridinyl, cinnolinyl and naphthyridinyl;

a 3-7 membered carbocyclic ring aromatic or nonaromatic;

wherein G is optionally substituted by one or more R₁, R₂ or R₃;

Q is

a carbocyclic ring chosen from naphthyl, benzocyclobutanyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl,benzocycloheptenyl, indanyl and indenyl;

a ring system chosen from benzoxazinyl, benzimidazolyl, benzothiazolyl,benzooxazolyl, benzofuranyl, benzopyranyl, benzodioxolyl, quinaldinyl,quinazolinyl, quinoxalinyl, isoquinolinyl, quinolinyl, indolyl,isoindolyl, indolinyl, purinyl, tetrahydroquinolinyl, indazolyl,imidazo-pyridinyl, pyrazolo-pyridinyl, pyrazolo-pyrimidinyl,pyrrolo-pyrimidinyl, pyrrolo-pyridinyl, pyrido-pyrazinyl,pyrido-pyrimidinyl, pyrido-oxazinyl, pyrido-thiazinyl, pyrido-oxazolyl,pyrido-thioxazolyl, pyrimido-pyrimidine, pteridinyl, cinnolinyl andnaphthyridinyl;

wherein each Q is optionally substituted with one to three Y,

each Y is independently chosen from

L-NR₅R₆ wherein L is a bond, —(CH₂)₁₋₅— or >C(O),

hydrogen, oxo, C₁₋₅ alkyl branched or unbranched, C₁₋₃ alkyl(OH), C₂₋₅alkenyl, C₁₋₃ acyl, heterocyclylC₀₋₃ alkyl wherein the heterocyclyl ischosen from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl andtetrahydrofuryl, heteroarylC₀₋₃ alkyl wherein the heteroaryl is chosenfrom pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl,triazolyl, tetrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzopyrazolyl, benzothiofuranyl, quinoxalinyl, quinazolinyl andindazolyl and arylC₀₋₃ alkyl,

wherein each Y is optionally substituted by one to three hydroxy, oxo,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl, C₁₋₅ alkoxycarbonyl, —NR₅R₆ orNR₅R₆—C(O)—;

each R₅ or R₆ is independently:

hydrogen, arylC₀₋₃ alkyl, C₃₋₇ cycloalkylC₀₋₃ alkyl, heterocyclylC₀₋₃alkyl or heterocyclylcarbonyl wherein the heterocyclyl is as hereinabovedescribed for Y, heteroarylC₀₋₃ alkyl or heteroarylcarbonyl wherein theheteroaryl is as hereinabove described for Y, C₁₋₃ acyl, aroyl or C₁₋₆branched or unbranched alkyl, each R₅ or R₆ is optionally substituted byC₁₋₅ alkoxy, hydroxy, mono- or di-C₁₋₃alkylaminocarbonyl, mono or diC₁₋₃alkylamino, mono or diC₁₋₃ alkylsulfonylamino or C₁₋₃ alkylsulfonyl;

each R₁ is independently:

C₁₋₁₀ alkyl branched or unbranched, wherein one or more C atoms areoptionally independently replaced by O, N or S(O)_(m), and wherein saidC₁₋₁₀ alkyl is optionally substituted with one to three C₃₋₁₀cycloalkyl, hydroxy, oxo, phenyl, naphthyl or halogen, or R₁ is

phenyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy orcycloheptyloxy each optionally substituted with one to three C₁₋₃ alkylgroups, nitrile, hydroxyC₁₋₃alkyl or aryl;

phenyloxy or benzyloxy each optionally substituted with one to threeC₁₋₃ alkyl groups, nitrile, hydroxyC₁₋₃alkyl or aryl;

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each beingoptionally substituted with one to three C₁₋₃ alkyl, nitrile,hydroxyC₁₋₃alkyl or aryl;

C₃₋₁₀ branched or unbranced alkenyl each being optionally substitutedwith one to three C₁₋₅ branched or unbranched alkyl, phenyl or naphthyl,

cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionallysubstituted with one to three C₁₋₃ alkyl groups;

morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranylor tetrahydrofuryl,

oxo, nitrile, halogen; or

C₃₋₆ alkynyl branched or unbranched carbon chain wherein one or moremethylene groups are optionally replaced by O, N or S(O)_(m) and whereinsaid alkynyl group is optionally independently substituted with one totwo oxo groups, hydroxy, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, oneor more C₁₋₄ alkyl optionally substituted by one or more halogen atoms,nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl,pyridinyl, tetrazolyl or mono- or di(C₁₋₃alkyl)amino;

each R₂ is independently:

a C₁₋₆ branched or unbranched alkyl optionally halogenated, C₁₋₆acyl,aroyl, C₁₋₄ branched or unbranched alkoxy optionally halogenated,halogen, methoxycarbonyl, C₁₋₄ alkyl-S(O)_(m) branched or unbranched orphenyl-S(O)_(m);

each R₃ is independently

C₁₋₆ branched or unbranched alkyl, arylC₀₋₆ alkyl, heteroarylC₀₋₆ alkyl,heterocyclyl C₀₋₆ alkyl each optionally substituted with one to threeC₁₋₃ alkyl groups, nitrile, hydroxyC₁₋₃alkyl or aryl;

amino wherein the nitrogen atom is optionally mono- or di-substituted byC₁₋₆ branched or unbranched alkyl, arylC₀₋₆ alkyl, heteroarylC₀₋₆ alkyland heterocyclyl C₀₋₆ alkyl;

J-S(O)_(m)—NR₇— wherein the nitrogen atom is covalently attached to G;

or R₃ is J-NR₇—C(O)—,

wherein

R₇ is hydrogen or C₁₋₃ alkyl;

J is chosen from C₁₋₆ branched or unbranched alkyl optionallysubstituted with 1 to 3 halogen atoms, arylC₀₋₆ alkyl, heteroarylC₀₋₆alkyl and heterocyclyl C₀₋₆ alkyl;

each m is independently 0, 1 or 2;

and X is O or S;

or the pharmaceutically acceptable derivatives thereof.

In yet still another embodiment of the invention there are providedcompounds of the formula (II) as described in the embodiment immediatelyabove and wherein:

G is a 6-membered monocyclic heteroaryl ring chosen from pyridinyl,pyrimidinyl, pyrazinyl and pyridazinyl;

phenyl, naphthyl, indanyl, indenyl or C₃₋₇ cycloalkyl;

wherein G is optionally substituted by one to three R₁, R₂ or R₃;

ring A and the phenyl ring to which it is fused form:

Q is

a ring system chosen from benzimidazolyl, benzothiazolyl, benzooxazolyl,benzisoxazolyl, benzofuranyl, benzofuranyl, benzodioxolyl, indolyl,isoindolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, purinyl,indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzopyranyl,benzoxazinyl, pyrido[2,3-b]oxazinyl, pyrido[2,3-b]pyrazinyl,pyrido[2,3-b]thiazinyl, pyrrolo[3,2-c]pyridinyl andpyrazolo[3,4-d]pyrimidinyl;

wherein each Q is optionally substituted with one to three Y,

R₁ is

C₁₋₁₀ alkyl, C₁₋₉ alkoxy each branched or unbranched and optionallysubstituted with one to three C₃₋₁₀ cycloalkyl, hydroxy, oxo, phenyl,naphthyl or halogen, morpholinyl, piperazinyl, piperidinyl,

or R₁ is

phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each beingoptionally substituted with one to three C₁₋₃ alkyl, nitrile,hydroxyC₁₋₃alkyl or aryl;

R₂ is

halogen, C₁₋₆ branched or unbranched alkyl or C₁₋₄ branched orunbranched alkoxy each optionally halogenated;

R₃ is J-S(O)_(m)—NR₇— wherein the nitrogen atom is covalently attachedto G and wherein J is chosen from a C₁₋₆ branched or unbranched alkyloptionally substituted with 1 to 3 halogen atoms, arylC₀₋₆ alkyl,heteroarylC₀₋₆ alkyl and heterocyclyl C₀₋₆ alkyl; and

X is O.

In another embodiment of the invention there are provided compounds ofthe formula (II) as described in the embodiment immediately above andwherein:

G is pyridinyl, phenyl, naphthyl, indanyl, indenyl or C₃₋₇ cycloalkyl;

wherein G is optionally substituted by one to three R₁, R₂ or R₃;

wherein each Y is independently chosen from

L-NR₅R₆ wherein L is a bond or —(CH₂)₁₋₅—;

hydrogen, oxo, C₁₋₅ alkyl branched or unbranched, C₁₋₃ acyl,heterocyclylC₀₋₃ alkyl wherein the heterocyclyl is chosen frommorpholinyl, piperazinyl, and pyrrolidinyl, heteroarylC₀₋₃ alkyl whereinthe heteroaryl is chosen from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl andoxazolyl, phenyl, naphthyl, benzyl and phenethyl,

wherein each Y is optionally substituted by one to three hydroxy, oxo,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl, C₁₋₅ alkoxycarbonyl or —NR₅R₆;

each R₅ or R₆ is independently:

hydrogen, phenyl, naphthyl, benzyl, phenethyl, C₃₋₇ cycloalkylC₀₋₃alkyl, heterocyclylC₀₋₃ alkyl or heterocyclylcarbonyl wherein theheterocyclyl is chosen from morpholinyl, tetrahydrofuranyl andtetrahydropyranyl, heteroarylC₀₋₃ alkyl or heteroarylcarbonyl whereinthe heteroaryl is chosen from pyridinyl, pyridinyl, pyrimidinyl,pyrazinyl and pyridazinyl, C₁₋₃ acyl, aroyl or C₁₋₆ branched orunbranched alkyl, each R₅ or R₆ is optionally substituted by C₁₋₅alkoxy, mono or diC₁₋₃ alkyl amino, mono or diC₁₋₃ alkylsulfonylamino orC₁₋₃ alkylsulfonyl;

R₁ is

C₁₋₁₀ alkyl, C₁₋₉ alkoxy each branched or unbranched and optionallysubstituted with one to three C₃₋₁₀ cycloalkyl, hydroxy, oxo, phenyl,naphthyl, fluoro, bromo or chloro or R₁ is morpholinyl or phenyl; and

R₃ is J-S(O)_(m)—NR₇— wherein the nitrogen atom is covalently attachedto G and wherein J is chosen from a C₁₋₆ branched or unbranched alkyloptionally substituted with 1 to 3 halogen atoms and arylC₀₋₆ alkyl.

In yet another embodiment of the invention there are provided compoundsof the formula (II) as described in the embodiment immediately above andwherein:

G is pyridinyl, phenyl, cyclopropyl or naphthyl each optionallysubstituted by one to three R₁, R₂ or R₃;

Q is chosen from imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,pyrido[2,3-b]oxazinyl, pyrido[2,3-b]pyrazinyl, pyrido[2,3-b]thiazinyl,pyrazolo[3,4-d]pyrimidinyl, isoquinolinyl, purinyl andpyrrolo[3,2-c]pyridinyl;

wherein each Q is optionally substituted with one to three Y,

wherein each Y is independently chosen from

L-NR₅R₆ wherein L is a bond or —(CH₂)₁₋₅—,

hydrogen, oxo, C₁₋₅ alkyl branched or unbranched, heterocyclylC₀₋₃ alkylwherein the heterocyclyl is chosen from morpholinyl, piperazinyl, andpyrrolidinyl, pyridinylC₀₋₃ alkyl or benzyl,

wherein each Y is optionally substituted by one to three hydroxy, oxo,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl or —NR₅R₆;

each R₅ or R₆ is independently:

hydrogen, phenyl, benzyl, C₃₋₆ cycloalkylC₀₋₃ alkyl, heterocyclylC₀₋₃alkyl or heterocyclylcarbonyl wherein the heterocyclyl is chosen frommorpholinyl, tetrahydrofuranyl and tetrahydropyranyl, pyridinylC₀₋₃alkyl, pyridinylcarbonyl, C₁₋₃ acyl, benzoyl or C₁₋₆ branched orunbranched alkyl optionally substituted by C₁₋₅ alkoxy, mono or diC₁₋₃alkyl amino, mono or diC₁₋₃ alkylsulfonylamino or C₁₋₃ alkylsulfonyl;

R₇ is hydrogen; and

J is C₁₋₆ branched or unbranched alkyl optionally substituted with 1 to3 halogen atoms.

In still another embodiment of the invention there are providedcompounds of the formula (II) as described in the embodiment immediatelyabove and wherein:

Q is chosen from:

R₁ is

morpholinyl, phenyl, CF₃, OCF₃, —C(CH₃)₃, —C(CH₂F)₃ or —CH₂C(CH₃)₃;

R₂ is

chloro, bromo, fluoro, C₁₋₄ branched or unbranched alkoxy, CF₃ or OCF₃;and

J is C₁₋₃ alkyl optionally substituted with 1 to 3 halogen atoms.

In yet still another embodiment of the invention there are providedcompounds of the formula (II) as described in the embodiment immediatelyabove and wherein:

G is:

In still another embodiment of the invention there are providedcompounds of the formula (II) as described in the embodiment immediatelyabove and wherein:

G is:

Y is independently chosen from

L-NR₅R₆ wherein L is a bond or —(CH₂)₁₋₃—,

C₁₋₅ alkyl branched or unbranched, morpholinylC₀₋₃ alkyl or benzyl; and

each R₅ or R₆ is independently:

hydrogen, phenyl, benzyl or C₃₋₆ cycloalkylC₀₋₃ alkyl.

Table I contains representative compounds of the invention which havebeen made by according to the general methods and examples in thesections below.

TABLE I

1-[4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol- 3-yl)-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-pyrrolo[3,2-c]pyridin-1-yl-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-3H-imidazo[4,5-b]pyridin-6-yl)- naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen- 1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl)-naphthalen- 1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)-naphthalen- 1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydro-4-lambda-4-pyrido[2,3-b][1,4]thiazin-7-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,4,4-trioxo-1,2,3,4-tetrahydro-4-lambda-6-pyrido[2,3-b][1,4]thiazin-7-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-ureido}-phenyl)- methanesulfonamide;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;

N-(3-{3-[4-(3-Benzyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-ureido}-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide;

N-{5 -tert-Butyl-2-methoxy-3-[3-(4-pyrrolo[3,2-c]pyridin-1-yl-naphthalen-1-yl)-ureido]-phenyl}- methanesulfonamide;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-pyrrolo[3,2-c]pyridin-1-yl-naphthalen-1-yl)-urea;

N-{5-tert-Butyl-3-[3-(4-imidazo[4,5-c]pyridin-3-yl-naphthalen-1-yl)-ureido]-2-methoxy-phenyl}- methanesulfonamide;

N-{5-tert-Butyl-3-[3-(4-imidazo[4,5-c]pyridin-1-yl-naphthalen-1-yl)-ureido]-2-methoxy-phenyl}- methanesulfonamide and thepharmaceutically acceptable derivatives thereof.

Table II contains representative compounds of the invention which can bemade by according to the general methods and examples in the sectionsbelow.

TABLE II

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[3-(2-morpholin-4-yl-ethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-naphthalen-1- yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[3-(2-dimethylamino-ethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(3-pyridin-2-ylmethyl-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen- 1-yl]-urea;

1-[4-(1-Benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)- urea;

1-[4-(2-Amino-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)- urea;

N-(6-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)- acetamide;

N-(6-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)- benzamide;

N-(6-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)- nicotinamide;

N-(6-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)- methanesulfonamide;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(3-methanesulfonyl-3H-imidazo[4,5-b]pyridin-6-yl)- naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-diethylaminomethyl-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-pyrrolidin-1-ylmethyl-3H-imidazo[4,5-b]pyridin-6-yl)- naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(4-methyl-piperazin-1-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-naphthalen- 1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,3-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl)- naphthalen-1-yl]-urea;

1-[4-(3-Benzyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)- naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-3-pyridin-2-ylmethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[3-(3,4-dimethoxy-benzyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[3-(2-dimethylamino-ethyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-isoquinolin-5-yl-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-purin-9-yl-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-purin-7-yl-naphthalen-1-yl)-urea;

1-[4-(6-Amino-purin-9-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-methylamino-purin-9-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-dimethylamino-purin-9-yI)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-cyclopropylamino-purin-9-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-purin-9-yl]-naphthalen-1- yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxy-ethylamino)-purin-9-yl]-naphthalen-1-yl}- urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino-ethylamino)-purin-9-yl]-naphthalen-1- yl}-urea;

1-[4-(6-Benzylamino-purin-9-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(pyridin-2-ylmethyl)-amino]-purin-9-yl}-naphthalen-1-yl)- urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxy-1-methyl-ethylamino)-purin-9-yl]- naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-phenyl-ethylamino)-purin-9-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-cyclopentylamino-purin-9-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-isopropylamino-purin-9-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-cyclohexylamino-purin-9-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-naphthalen- 1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-furan-3-ylamino)-purin-9-yl]-naphthalen- 1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-pyrrolidin-1-yl-purin-9-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-yl-purin-9-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-yl)-purin-9-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-dimethylamino-ethyl)-methyl-amino]-purin-9-yl}- naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-morpholin-4-yl-ethylamino)-purin-9-yl]-naphthalen-1- yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-ethylamino-2-methyl-purin-9-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-methyl-6-(2-morpholin-4-yl-ethylamino)-purin-9-yl]- naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-cyclopropylamino-2-methyl-purin-9-yl)-naphthalen-1- yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,6-dioxo-1,2,3,6-tetrahydro-purin-9-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-pyrazolo[3,4-d]pyrimidin-1-yl-naphthalen-1-yl)-urea and the pharmaceuticallyacceptable derivatives thereof.

In another distinct embodiment, there is also provided the followingcompound possessing anticytokine activity:

In all the compounds disclosed hereinabove in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

Any compounds of this invention containing one or more asymmetric carbonatoms may occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. All such isomericforms of these compounds are expressly included in the presentinvention. Each stereogenic carbon may be in the R or S configuration,or a combination of configurations.

Some of the compounds of formulas (I) & (II) can exist in more than onetautomeric form. The invention includes all such tautomers.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₄alkoxy” is a C₁₋₄alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, and butoxy. All alkyl, alkenyl and alkynylgroups shall be understood as being C₁₋₁₀ branched or unbranched wherestructurally possible and unless otherwise specified. Other morespecific definitions are as follows:

The term “aroyl” as used in the present specification shall beunderstood to mean “benzoyl” or “naphthoyl”.

The term “carbocycle” shall be understood to mean an aliphatichydrocarbon radical containing from three to twelve carbon atoms.Carbocycles include hydrocarbon rings containing from three to tencarbon atoms. These carbocycles may be either aromatic or non-aromaticring systems. The non-aromatic ring systems may be mono- orpolyunsaturated. Preferred carbocycles unless otherwise specifiedinclude but are not limited to cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl,phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl,tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl.

The term “heterocycle” refers to a stable nonaromatic 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 memberedbicyclic heterocycle radical which may be either saturated orunsaturated. Each heterocycle consists of carbon atoms and one or more,preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure. Preferred heterocyclesinclude but are not limited to, for example pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl,morpholinyl, tetrahydropyranyl, dioxanyl, oxazolinyl, thiazolinyl,imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl,tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl,thiomorpholinyl, thiazolidinyl.

The term “heteroaryl” shall be understood to mean an aromatic 5-8membered monocyclic or 8-11 membered bicyclic ring containing 1-4heteroatoms chosen from N, O and S. Included are the partially or fullysaturated derivates thereof. Such heteroaryls unless otherwise specifiedinclude: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl,triazolyl, tetrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzopyrazolyl, benzothiofuranyl, quinoxalinyl, quinazolinyl andindazolyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

In all alkyl groups or carbon chains where one or more carbon atoms areoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by oxo to result indefinitions such as but not limited to: acyl, alkoxycarbonyl,alkylthiosulfone, alkylthiosulfonyl, amido etc.

The term “aryl” as used herein unless otherwise specified shall beunderstood to mean aromatic carbocycle or heteroaryl as defined herein.

Terms which are analogs of the above cyclic moieties such as aryloxy,heterocyclyloxy or heteroaryl amine shall be understood to mean an aryl,heteroaryl, heterocycle as defined above attached to it's respectivegroup.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen. Forexample, if Y is —S—C₁₋₆ alkyl, unless otherwise specified, this shallbe understood to include —S(O)—C₁₋₆ alkyl and —S(O)₂—C₁₋₆ alkyl.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the invention.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formulas (I) & (II). A “pharmaceutically acceptablederivative” refers to any pharmaceutically acceptable salt or ester of acompound of this invention, or any other compound which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound of this invention, a pharmacologically activemetabolite or pharmacologically active residue thereof. Apharmacologically active metabolite shall be understood to mean anycompound of the formula(I) capable of being metabolized enzymatically orchemically. This includes, for example, hydroxylated or oxidizedderivative compounds of the formulas (I)/(II).

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.Other acids, such as oxalic acid, while not themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of this invention and theirpharmaceutically acceptable acid addition salts. Salts derived fromappropriate bases include alkali metal (e.g., sodium), alkaline earthmetal (e.g., magnesium), ammonium and N-(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, the compounds of this invention include prodrugs ofcompounds of the formulas (I) & (II). Prodrugs include those compoundsthat, upon simple chemical transformation, are modified to producecompounds of the invention. Simple chemical transformations includehydrolysis, oxidation and reduction. Specifically, when a prodrug ofthis invention is administered to a patient, the prodrug may betransformed into a compound of formulas (I) & (II), thereby impartingthe desired pharmacological effect.

Methods of Use

In accordance with the invention, there are provided methods of usingthe compounds of the formulas (I) & (II). The compounds of the inventioneffectively block inflammatory cytokine production from cells. Theinhibition of cytokine production is an attractive means for preventingand treating a variety of cytokine mediated diseases or conditionsassociated with excess cytokine production, e.g., diseases andpathological conditions involving inflammation. Thus, the compounds areuseful for the treatment of diseases and conditions as described in theBackground section, including the following conditions and diseases:

osteoarthritis, atherosclerosis, contact dermatitis, bone resorptiondiseases, reperfusion injury, asthma, multiple sclerosis, Guillain-Barresyndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versushost disease, systemic lupus erythematosus and insulin-dependentdiabetes mellitus, rheumatoid arthritis, toxic shock syndrome,Alzheimer's disease, toxic shock syndrome, diabetes, inflammatory boweldiseases, acute and chronic pain as well as symptoms of inflammation andcardiovascular disease, stroke, myocardial infarction, alone orfollowing thrombolytic therapy, thermal injury, adult respiratorydistress syndrome (ARDS), multiple organ injury secondary to trauma,acute glomerulonephritis, dermatoses with acute inflammatory components,acute purulent meningitis or other central nervous system disorders,syndromes associated with hemodialysis, leukopherisis, granulocytetransfusion associated syndromes, and necrotizing entrerocolitis,complications including restenosis following percutaneous transluminalcoronary angioplasty, traumatic arthritis, sepsis, chronic obstructivepulmonary disease and congestive heart failure.

In addition, the compounds of the invention being inhibitors of cytokineproduction are expected to block inducible cyclooxygenase (COX-2)expression. COX-2 expression has been shown to be increased by cytokinesand it is believed to be the isoform of cyclooxygenase responsible forinflammation (M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992,89, 4888.) Accordingly, the present novel compounds would be expected toexhibit efficacy against those disorders currently treated with COXinhibitors such as the familiar NSAIDs. These disorders include acuteand chronic pain as well as symptoms of inflammation and cardiovasculardisease.

As discussed in the Background of the Invention, IL-8 plays a role inthe influx of neutrophils into sites of inflammation or injury.Therefore, in a yet further aspect of the invention, the compounds ofthe invention may be useful in the treatment of diseases mediatedpredominantly by neutrophils such as stroke and myocardial infarction,alone or following thrombolytic therapy, thermal injury, adultrespiratory distress syndrome (ARDS), multiple organ injury secondary totrauma, acute glomerulonephritis, dermatoses with acute inflammatorycomponents, acute purulent meningitis or other central nervous systemdisorders, hemodialysis, leukopherisis, granulocyte transfusionassociated syndromes, and necrotizing enterocolitis.

For therapeutic use, the compounds of the invention may be administeredin any conventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutic compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 5%, but more preferablyat least about 20%, of a compound of formulas (I) & (II) (w/w) or acombination thereof. The optimum percentage (w/w) of a compound of theinvention may vary and is within the purview of those skilled in theart.

Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

As mentioned above, dosage forms of the compounds of this inventioninclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms areknown. Reference in this regard may be made to H. C. Ansel and N. G.Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5thed., Lea and Febiger (1990), Cappola et al. U.S. application Ser. No.09/902,822 and U.S. provisional application ser. No. 60/313,527. Dosagelevels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 1-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. Reference in this regard may also be made to U.S. provisionalapplication No. 60/339,249. For oral doses, up to 2000 mg/day may berequired. As the skilled artisan will appreciate, lower or higher dosesmay be required depending on particular factors. For instance, specificdosage and treatment regimens will depend on factors such as thepatient's general health profile, the severity and course of thepatient's disorder or disposition thereto, and the judgment of thetreating physician.

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating preferred embodiments of this invention, and are not to beconstrued as limiting the scope of the invention in any way.

The examples which follow are illustrative and, as recognized by oneskilled in the art, particular reagents or conditions could be modifiedas needed for individual compounds without undue experimentation.Starting materials used in the scheme below are either commerciallyavailable or easily prepared from commercially available materials bythose skilled in the art.

General Synthetic Methods

The invention additionally provides for methods of making the compoundsof the formulas (I) & (II). The compounds of the invention may beprepared by the general methods and examples presented below, andmethods known to those of ordinary skill in the art. Further referencein this regard may be made to U.S. Pat. No. 6,297,381, U.S. applicationSer. Nos. 09/505,582, 09/484,638, 09/735,160, 09/902,085, 09/698,442,09/834,797, 09/611,109, U.S. provisional application Nos. 60/206,327,60/216,283, 60/295,909, 60/293,600, 60/291,425, 60/283,642 and60/268,841. Each of the aforementioned are incorporated herein byreference in their entirety.

In all schemes “G” in the formulas shown below shall have the meaning of“G” in the formulas (I) and (II) of the invention described hereinabove.“G′” (G prime) shall have the meaning of

in the formulas (I) and (II) or a precursor of that moiety.

The compounds of the invention may be prepared by Method A, B, C or D asillustrated in Scheme I, preferably Method C.

In Method A, a mixture of an arylamine of formula III and anarylisocyanate of formula IV is dissolved in a non-protic, anhydroussolvent such as THF, ether, toluene, dioxane or ethyl acetate. Thepreferred solvent is THF. The mixture is stirred at between 0-45° C.,preferably at 25° C., for 2-24 h, and the volatiles are removed.Purification of the residue by recrystallization from an appropriatesolvent such as ethyl acetate/hexanes, ethyl acetate/MeOH, THF/petroleumether, EtOH/water or by silica gel chromatography, using for example,hexanes and ethyl acetate as eluents, provides the product of formula Ior II or precursors thereof.

In Method B, an arylamine of formula III is dissolved in a halogenatedsolvent, such as methylene chloride, chloroform or dichloroethane. Thepreferred solvent is methylene chloride. The mixture is diluted withaqueous alkali, such as sodium bicarbonate or potassium carbonate,cooled in an ice bath and phosgene is added. The mixture is vigorouslystirred for 5-30 min, with 10 min being preferable. The organic layer isdried, with agents such as MgSO₄ or Na₂SO₄, and the volatiles removed toprovide the corresponding isocyanate. The isocyanate and arylamine IVare mixed in a non-protic, anhydrous solvent such as THF, ether,toluene, dioxane, methylene chloride or ethyl acetate. The preferredsolvent is THF. The mixture is stirred at between 0-45° C., preferablyat 25° C., for 2-24 h, and the volatiles are removed. Purification ofthe residue by recrystallization or by silica gel chromatography, asabove, provides the product of formula I or II or precursors thereof.

The required isocyanate may also be prepared from the carboxylic acidG-CO₂H by reaction with a chloroformate, such as ethyl chloroformate, inthe presence of a suitable base, such as triethylamine, in a suitablesolvent, such as THF at about 0° C. The resulting mixed anhydride istreated with an aqueous solution of sodium azide. Heating a solution ofthe resulting acyl azide in a suitable solvent, such as toluene, atabout reflux, results in a Curtius rearrangement, providing theisocyanate G-N═C═O in situ.

In Method C, an arylamine of formula III is dissolved in a suitablesolvent such as a halogenated solvent which includes methylene chloride,chloroform or dichloroethane. The preferred solvent is methylenechloride. A suitable base such as triethylamine may be added, followedby an alkyl or aryl chloroformate, such as t-butyl chloroformate orphenyl chloroformate (shown). The mixture is stirred at between 0-85°C., preferably at reflux temperature, for 2-24 h, and the volatiles areremoved providing carbamate VI. The carbamate and arylamine V are mixedin a non-protic, anhydrous solvent such as DMSO, THF, ether, toluene,dioxane, methylene chloride or ethyl acetate. The mixture is stirred atbetween 0-110° C., preferably at between about 50° C. and refluxtemperature, for 2-24 h, and the volatiles are removed. Purification ofthe residue as above provides the product of formula I or II orprecursors thereof. This process can also be performed in the reversesense as illustrated by Method D.

Arylamine intermediates of formula III are either commercially availableor can be made by methods known to those skilled in the art. Furtherreference in this regard may be made to the U.S. applications cited inthe first paragraph of this section. Methods by which intermediates IVand V may be prepared are also known to those skilled in the art. Someof these methods are exemplified below.

SYNTHETIC EXAMPLES Example 1 Synthesis of1-(4-aminonaphthalen-1-yl)pyrrolo[3,2-c]pyridine

In a dry round-bottom flask under inert atmosphere and equipped with amagnetic stirrer bar was added boron trifluoride etherate (2.65 mL,20.93 mmol, 1.5 equiv.). To this reagent cooled to 0° C. a solution on4-nitro-1-naphthylamine (2.626 g, 13.95 mmol, 1 equiv.) in 39 mLanhydrous DME was slowly added via syringe. 15 min after the additionwas complete, a solution of tert-butyl nitrite (2.00 mL, 16.74 mmol, 1.2equiv.) in 15 mL anhydrous DME was added dropwise via syringe. Themixture was allowed to reach room temperature and stir 1 h. The reactionwas then cooled to 0° C. without stirring. The precipitated green/golddiazonium tetrafluoroborate salt was collected by filtration (3.858 g,13.44 mmol, 96%).

The nitronaphthalene diazonium tetrafluoroborate salt from above (3.448g, 12.0 mmol, 1 equiv.) was suspended in 100 mL xylenes, heated toreflux for 1 h, then allowed to cool back to room temperature. Water wasthen added and the product extracted twice with ether. The combinedextracts were dried (MgSO₄), filtered, and the solvents were removed invacuo. The crude product was purified by column chromatography on SiO₂using 10% EtOAc in hexanes as eluent, providing 1.95 g of4-fluoro-1-nitronaphthalene (10.20 mmol, 85% yield).

3-Methyl-4-nitro-pyridine-N-oxide (5.34 g, 34.7 mmol, 1 equiv.) andN,N-dimethylformamide diethyl acetal (10.5 mL, 61.4 mmol, 1.8 equiv.)were combined in 50 mL anhydrous DMF and heated to 120° C. for 3 h. Thereaction was allowed to cool back to room temperature and the DMFsolvent was removed in vacuo. The residue was treated with ˜80 mLtoluene, which was then removed in vacuo as well. Finally the residuewas mixed with benzene and filtered. The desired vinyl amine wasobtained as a dark purple solid (6.74 g, 32.2 mmol, 93%), which was usedas is in the next step.

The vinyl amine from above (3.37 g, 16.1 mmol, 1 equiv.) and 1.75 mL ofwater were mixed in 50 mL EtOH. Ammonium formate (4.56 g, 72.5 mmol) and10% palladium-on-carbon (600 mg) were added and the mixture was heatedto a gentle reflux for 1 h. TLC and MS (ES+) revealed no startingmaterial but showed the presence of two major components, the desired5-aza-indole and its N-oxide. The reaction was left stirring for afurther 2 h after more ammonium formate and more palladium catalyst wereadded. Finally the reaction was cooled to room temperature, filtered andsolvents removed in vacuo. 5% NaOH aqueous solution was added and themixture was extracted with EtOAc. The combined organics were dried(MgSO₄), filtered, and the solvent was removed in vacuo, providing 0.555g of desired 5-aza-indole (4.70 mmol, 29% yield).

The 5-aza-indole from above (425 mg, 3.60 mmol, 1 equiv.) was added topotassium tert-butoxide (404 mg, 3.60 mmol, 1 equiv.) in 7.0 mLanhydrous DMSO at room temperature. When all solids had completelydissolved (brown color present), 4-fluoro-1-nitro-naphthalene from above(688 mg, 3.60 mmol, 1 equiv.) was added and the mixture was heated to60° C. for 15 min. The reaction was allowed to cool, quenched withsaturated aqueous NaHCO₃ solution and extracted repeatedly with EtOAc.The combined extracts were washed twice with water and once with brine,then dried (MgSO₄), filtered and the solvent removed in vacuo. Thedesired product was purified by a short column of SiO₂, using 3% MeOH indichloromethane as eluent providing 650 mg of the4-indolo-1-nitronaphthalene derivative (2.25 mmol, 62%).

The 4-indolo-1-nitronaphthalene from above (167 mg, 0.58 mmol, 1 equiv.)was dissolved in 12 mL EtOH and 12 mL EtOAc. Ammonium formate (218 mg,3.46 mmol, 6 equiv.) and 10% palladium-on-carbon (60 mg) were then addedand the mixture was gently refluxed for 20 min. The reaction was allowedto cool, filtered, the catalyst washed with with EtOAc and solventsremoved in vacuo providing a light tan foam (206 mg). This was taken upin dichloromethane and filtered through 0.45 um membrane to remove leftover traces of ammonium formate. Concentration of the filtrate gave 142mg (0.55 mmol, 94%) of the title compound.

Example 2 Synthesis of1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-pyrrolo[3,2-c]pyridin-1-yl-naphthalen-1-yl)-urea

(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester (144mg, 0.411 mmol, 1.1 equiv.) and1-(4-aminonaphthalen-1-yl)pyrrolo[3,2-c]pyridine (Example 1) (97 mg,0.374 mmol, 1 equiv.) were combined in 2 mL anhydrous DMSO. The mixturewas stirred under inert atmosphere for 1.5 h, then heated to 60° C. for0.5 h. The reaction was allowed to cool, quenched with 5% aqueous NaOHand extracted with EtOAc three times. The combined organic extracts werewashed with water, then brine. They were then dried (MgSO₄), filtered,and the solvents were removed in vacuo. The residue was purified bycolumn chromatography using 3-4% MeOH in dichloromethane providing 161mg title compound (0.313 mmol, 84%) as a glassy solid.

Example 3 Synthesis of1-(5-tert-butyl-2-methoxy-phenyl)-3-(4-pyrrolo[3,2-c]pyridin-1-yl-naphthalen-1-yl)-urea

4-tert-Butyl-o-anisidine (54 mg, 0.301 mmol, 1 equiv.) was dissolved in15 mL dichloromethane and 15 mL of saturated aqueous NaHCO₃ solution wasadded. The biphasic mixture was cooled to 0° C. and phosgene (˜2 Msolution in toluene, 0.75 mL) was added to the organic layer via syringein one portion, without stirring. The mixture was then stirredvigorously for 10 min, then the layers were separated. The aqueous layerwas extracted once with dichloromethane and the combined organics weredried (Na₂SO₄), filtered and most of the dichloromethane was removed invacuo, leaving the toluene. To this isocyanate residue was then added1-(4-aminonaphthalen-1-yl)pyrrolo[3,2-c]pyridine (Example 1) (77 mg,0.297 mmol, 1 equiv.) dissolved in 5 mL anhydrous THF. The mixture wasleft to stir at room temperature for 2 h, then the solvents were removedin vacuo. The residue was purified by column chromatography on SiO₂using dichloromethane/MeOH eluent mixtures. The isolated enrichedfraction was further purified by reverse-phase preparative HPLC toprovide 20 mg of the title compound as a white foam.

Example 4 Synthesis ofN-{5-tert-butyl-2-methoxy-3-[3-(4-pyrrolo[3,2-c]pyridin-1-yl-naphthalen-1-yl)-ureido]-phenyl}-methanesulfonamide

N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (75 mg,0.266 mmol, 1 equiv.) was dissolved in 20 mL dichloromethane and 20 mLof saturated aqueous NaHCO₃ solution was added. The biphasic mixture wascooled to 0° C. and phosgene (˜2 M solution in toluene, 0.44 mL) wasadded to the organic layer via syringe in one portion without stirring.The mixture was then stirred vigorously for 10 min, then the layers wereseparated. The aqueous layer was extracted once with dichloromethane andthe combined organics were dried (Na₂SO₄), filtered and most of thedichloromethane was removed in vacuo, leaving the toluene. To thisisocyanate residue was then added1-(4-aminonaphthalen-1-yl)pyrrolo[3,2-c]pyridine (Example 1) (46 mg,0.177 mmol, 1 equiv.) dissolved in 5 mL anhydrous THF. The mixture wasleft to stir at room temperature overnight, then the solvents wereremoved in vacuo. The residue was purified by column chromatography onSiO₂ using dichloromethane/MeOH eluent mixtures. The title compound (34mg) was isolated as a pink foam.

Example 5 Synthesis of1-(4-aminonaphthalen-1-yl)-1H-imidazo[4,5-c]pyridine (5a) and1-(4-aminonaphthalen-1-yl)-1H-imidazo[5,4-c]pyridine (5b)

5-Aza-benzimidazole (312 mg, 2.62 mmol, 1 equiv.) in 5 mL anhydrous DMSOwas treated with potassium tert-butoxide (294 mg, 2.62 mmol, 1.0 equiv.)at room temperature. When the mixture was completely homogeneous,4-fluoro-1-nitro-naphthalene (500 mg, 2.62 mmol, 1 equiv.) was added inone portion and the mixture was heated to 60° C. for 0.5 h. The reactionwas allowed to cool, then quenched with dilute aqueous NaHCO₃ solution.The product was extracted with a mixture of EtOAc, THF and acetone. Theorganic extracts were washed with water and brine, then dried (Na₂SO₄),filtered and the solvents removed in vacuo. ¹H NMR revealed a 1:1 ratioof regioisomers. The products were purified by column chromatography onSiO₂ using EtOAc/MeOH eluent mixtures.1-(4-Nitro-naphthalen-1-yl)-1H-imidazo[5,4-c]pyridine was isolated athigh Rf and 1-(4-nitro-naphthalen-1-yl)-1H-imidazo[4,5-c]pyridine atlower Rf, and overlapping fractions were in between. The overall yieldwas 357 mg (47%). Each nitro-naphthalene from above (˜100 mg, 0.4 mmol)was separately dissolved in 10 mL EtOAc and 5 mL of MeOH. Ammoniumformate was then added (100 mg, 1.6 mmol or 4 equiv.) and 10%palladium-on-carbon (˜60 mg). The mixture was stirred for 0.5 h at 50°C., then allowed to cool, filtered through diatomaceous earth and thesolvents were removed in vacuo to afford ˜80 mg of each naphthyl-amine5a and 5b, which could be coupled with anilines or pyrazolamines to formureas by the procedures described in Examples 2-4 above.

Example 6 Synthesis of 7-(4-amino-naphthalen-1-yl)-7H-purine (6a) and9-(4-amino-naphthalen-1-yl)-9H-purine (6b)

Purine (137 mg, 1.14 mmol, 1 equiv.) in 2.0 mL anhydrous DMSO wastreated with potassium tert-butoxide (128 mg, 1.14 mmol, 1 equiv.) atroom temperature. When the solution was completely homogeneous,4-fluoro-1-nitro-naphthalene (137 mg, 1.14 mmol, 1 equiv.) was added inone portion and the mixture was heated to 60° C. for 15 min. Thereaction was allowed to cool, quenched with dilute aqueous NaHCO₃solution (50 mL) and the product was collected by filtration to affordapproximately a 4:1 ratio of regioisomers favoring7-(4-nitro-naphthalen-1-yl)-7H-purine over9-(4-nitro-naphthalen-1-yl)-9H-purine. These regioisomers were separatedat this stage by column chromatography on SiO₂ using hexanes/EtOAceluent mixtures, the major isomer eluting at lower Rf. Reductions toform 6a and 6b and couplings to form ureas were performed by proceduresanalogous to those described in Examples above.

Other substituted purines (for example 3-chloro-purine) can be reactedin an analogous fashion and functionalized further to introduce forexample 3-thioalkyl, 3-alkoxy, 3-alkyl or aryl, 3-alkyl- or aryl-aminogroups on the purine moiety.

Example 7 Synthesis of7-(4-amino-naphthalen-1-yl)-1H-pyrido[2,3-b][1,4]oxazin-2-onehydrochloride

2-Hydroxy-3-nitro-5-bromopyridine (10 g) was combined with 25 mL ofphosphorus oxychloride and 5 g of phosphorus pentachloride. The mixturewas heated to 110° C. for 2 h, then cooled to room temperature andpoured into ice-water and stirred 30 min. The mixture was extracted withCHCl₃, then the combined organics were dried (MgSO₄) and concentrated invacuo. Purification by chromatography through a short plug of SiO₂,eluting with 4:1 hexanes:EtOAc afforded 6.72 g of5-bromo-2-chloro-3-nitro-pyridine.

The 4-Boc-amino-naphth-1-yl boronic acid (0.271 g, 0.944 mmol) and thechloropyridine intermediate from above (0.213 g, 0.899 mmol) werecombined in 3 mL of DME and 3 mL of 2M aqueous Na₂CO₃ solution wasadded. The biphasic mixture was purged with nitrogen for 10 min.Palladium tetrakis(triphenylphosphine) catalyst (0.104 g, 0.089 mmol)was then added and the mixture was heated at 65° C. for 4 h, then cooledto room temperature, diluted with EtOAc, washed with water and brine,and dried (MgSO₄). The coupled product was purified by flashchromatography on SiO₂ using 3:1 hexanes:EtOAc.

To sodium hydride (60% in oil, 104 mg, 2.61 mmol) suspended in 3 mLanhydrous DMF at 0-5° C., methl glycolate (0.19 mL, 2.51 mmol) was addeddropwise. The mixture was stirred for 90 min, then a solution of thenaphthyl-chloro-pyridine from above (0.334 g, 0.837 mmol) in 2 mL DMFwas added. The mixture was stirred for 30 min, then quenched with 2 mLof AcOH and partitioned between water and Et₂O. The ether layer waswashed with water, saturated aqueous NaHCO₃, brine, and dried (MgSO₄).The solvent was removed in vacuo, and the residue was purified bychromatography through a plug of SiO₂ with 2:1 hexanes:EtOAc eluent toprovide 0.248 g (65%) of the desired ester.

A mixture of the above ester (0.234 g, 0.516 mmol), 10% palladium-oncarbon (0.02 g) and ammonium formate (0.195 g, 3.10 mmol) in 8 mL EtOHwas heated at 90° C. for 1 h, then cooled to room temperature. It wasthen diluted with EtOAc, filtered through diatomaceous earth, washedwith water and brine, then dried (MgSO₄). After the solvent was removedin vacuo, the residue was taken up in 1,4-dioxane (5 mL) and treatedwith HCl in dioxane (4N, 3 mL). The mixture was heated at 70° C. for 3h. MeOH (8 mL) was then added and the mixture was heated for another 45min. Concentration in vacuo and trituration with Et₂O afforded the titlecompound (0.167 g, 99% yield).

Example 8 Synthesis of1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl)-urea

To 4-tert-butyl-o-anisidine (0.035 g, 0.198 mmol) in 2 mLdichloromethane and 2 mL saturated aqueous NaHCO₃ at 0° C., phosgene (˜2M in toluene, 0.21 mL, 0.40 mmol) was added via syringe to the organiclayer in one portion, while not stirring. The resulting mixture wasstirred vigorously for 10 min, then the organic layer was separated anddried (MgSO₄), filtered and concentrated in vacuo. To the resultingisocyanate solution was added a solution of7-(4-amino-naphthalen-1-yl)-1H-pyrido[2,3-b][1,4]oxazin-2-onehydrochloride (Example 7) (72 mg, 0.220 mmol) and diisopropyl ethylamine(42 uL, 0.242 mmol) in 2 mL anhydrous THF. This mixture was stirredovernight, then diluted with EtOAc, washed with water and brine, dried(MgSO₄), filtered and the solvents removed in vacuo. The residue waspurified by preparative HPLC to afford 12 mg of the title compound,m.p.>200° C.

Example 9 Synthesis of1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl)-urea

5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester(0.035 g, 0.099 mmol),7-(4-amino-naphthalen-1-yl)-1H-pyrido[2,3-b][1,4]oxazin-2-onehydrochloride (Example 7) (0.036 g, 0.11 mmol) and diisopropylethylamine (100 uL, 0.57 mmol) were combined in 1.5 mL anhydrous DMSO.The mixture was stirred at 60° C. under inert atmosphere for 5 h, thenallowed to cool and quenched with water and extracted with EtOAc threetimes. The combined organic extracts were washed with brine, then dried(MgSO₄), filtered, and the solvents were removed in vacuo. The residuewas purified by preparative HPLC providing 3 mg of the title compound,m.p.>200° C.

Example 10 Synthesis of1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-naphthalen-1-yl]-urea

A mixture of 4-(2-chloro-3-nitropyridin-3-yl)-N-Boc-naphth-1-yl amine(0.62 g) and 4 mL of 4 N HCl in 1,4-dioxane in 10 mL dioxane was stirredat room temperature overnight. The reaction was diluted with ether andthe resulting precipitate filtered and dried in vacuo. To thisnaphthylamine hydrochloride (0.201 g, 0.542 mmol) in 5 mLdichloromethane and 5 mL saturated aqueous NaHCO₃ solution at 0° C.,phosgene (˜2M in toluene, 0.71 mL, 1.35 mmol) was added via syringe tothe organic layer in one portion, while not stirring. The resultingmixture was stirred vigorously for 15 min, then the organic layer wasseparated, dried (MgSO₄), filtered and concentrated in vacuo. To theresulting isocyanate solution was added a solution of thetert-butyl-o-anisidine (0.097 g, 0.542 mmol). This mixture was stirred 4h at room temperature, then concentrated in vacuo and purified by flashchromatography using 35% EtOAc in hexanes as eluent to afford thedesired urea.

Glycine tert-butyl ester hydrochloride (0.044 g, 0.263 mmol) anddiisopropyl ethylamine (0.14 mL, 0.788 mmol) were mixed in 2 mLanhydrous DMF. To this mixture was added the urea from above (0.106 g,0.210 mmol). The reaction was stirred at room temperature overnight,diluted with water and the resulting solid was filtered and dried invacuo.

To the solid from above (0.108 g) and ammonium formate (68 mg) in 2 mLEtOH was added 10% palladium-on-carbon (15 mg). The mixture was heatedat 60° C. for 15 min, cooled to room temperature, diluted with EtOAc andfiltered. The organics were washed with water, then brine, then dried(MgSO₄). The residue was diluted with 3 mL EtOH and 2 mL 4 N HCl in1,4-dioxane and heated at 75° C. for 90 min. The reaction was cooled toroom temperature and concentrated in vacuo. The residue was diluted withEtOAc, washed with saturated aqueous NaHCO₃, brine, and dried (MgSO₄).The residue was diluted with acetonitrile and filtered to afford thetitle compound (28 mg), m.p.>230° C.

Example 11 Synthesis of1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(4,4-dioxo-3,4-dihydro-2-oxo-1H-4λ⁶-pyrido[2,3-b][1,4]thiazin-7-yl)-naphthalen-1-yl]-urea

4-(2-chloro-3-nitropyridin-3-yl)-naphth-1-yl amine dihydrochloride(0.238 g, 0.642 mmol), ethyl thioglycolate (70 uL, 0.642 mmol) anddiisopropyl ethylamine (0.45 mL, 2.57 mmol) were combined in 4 mL DMFand stirred at room temperature overnight. The reaction mixture was thendiluted with water and the product extracted with Et₂O. The organiclayer was washed with water and brine, then dried (MgSO₄) providing 0.23g of the desired thioether.

The thioether from above (0.23 g, 0.601 mmol), ammonium formate (0.15 g,2.40 mmol) and 10% palladium-on-carbon (200 mg) were combined in 5 mLEtOH and 1 mL EtOAc. The mixture was heated at 90° C. for 24 h, cooledto room temperature and filtered through diatomaceous earth. Thefiltrate was diluted with EtOAc, washed with water and brine, dried(MgSO₄), filtered, and the solvents were removed in vacuo, providing thedesired pyrido-thioxazin-2-one (161 mg).

To 4-tert-butyl-o-anisidine (84.5 mg, 0.472 mmol) in 3 mLdichloromethane and 3 mL saturated aqueous NaHCO₃ at 0-5° C., phosgene(˜2 M in toluene, 0.62 mL, 1.18 mmol) was added in one portion, to theorganic layer, via syringe, while not stirring. The mixture was stirredvigorously for 15 min, then the organic layer was separated, dried(MgSO₄) and concentrated in vacuo. The residue was then diluted with 2mL anhydrous THF, cooled to 0° C., and treated with thepyrido-thioxazin-2-one from above (0.145 g, 0.472 mmol) dissolved in 1mL anhydrous THF. The mixture was allowed to reach room temperature andstir overnight. The solvent was then removed in vacuo, and the productwas purified by flash chromatography on SiO₂ using 1:1 hexanes:EtOAc aseluent, providing 0.137 g of the desired urea which was further purifiedby reverse-phase preparative HPLC, providing the sulfoxide, m.p.188-190° C.

The sulfoxide from above (0.044 g, 0.0859 mmol), dissolved in 2 mL THF,was treated with m-CPBA (60-65%, 0.022 g, 0.0859 mmol) and the mixturewas stirred at room temperature overnight. It was then diluted withEtOAc, washed with aqueous Na₂S₂O₅, with saturated NaHCO₃, then withbrine, then dried (MgSO₄) and concentrated in vacuo. The residue waspurified by reverse-phase preparative HPLC providing the sulfoxide,m.p.>240° C.

The sulfoxide from above (0.052 g, 0.101 mmol) was dissolved in 2 mL THFand treated with m-CPBA (60-65%, 0.037 g, 0.213 mmol) at roomtemperature. The mixture was stirred for 2 days, then treated withanother 30 mg of m-CPBA and stirred one day. The mixture was thendiluted with EtOAc, washed with aqueous Na₂S₂O₅, with saturated NaHCO₃,then with brine, then dried (MgSO₄) and concentrated. The residue waspurified by reverse-phase preparative HPLC providing the title compound,m.p.>209-211° C.

Example 12 Synthesis ofN-(3-{3-[4-(3-Benzyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-ureido}-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide

To 4-(2-chloro-3-nitropyridin-3-yl)-naphth-1-yl amine dihydrochloride(0.203 g, 0.544 mmol) in 5 mL dichloromethane and 5 mL saturated aqueousNaHCO₃ at 0-5° C., phosgene (2 M in toluene, 0.72 mL, 1.37 mmol) wasadded in one portion to the organic layer, via syringe, while notstirring. The mixture was stirred vigorously for 15 min, then theorganic layer was separated and dried (MgSO₄) and concentrated in vacuo.The residue was then diluted with 2 mL anhydrous THF and treated withN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (0.148 g,0.544 mmol) dissolved in 5 mL anhydrous THF. The mixture was allowed toreach room temperature and stir overnight. The solvent was then removedin vacuo, and the product was purified by flash chromatography on SiO₂using 1:1 hexanes:EtOAc as eluent, providing 0.050 g of the desired ureaproduct.

Racemic benzyl-2-hydroxy-3-phenyl-propionate (0.094 mL, 0.418 mmol) wasadded to NaH (60% in oil, 18 mg) in 2 mL anhydrous DMF at 0-5° C. Afterstirring for 1 h, the above urea was added (0.050 g, 0.0837 mmol). Themixture was stirred for 2.5 h at 0-5° C., then at room temperature for 1h, then diluted with AcOH and ether. The organic layer was washed withwater, aqueous NaHCO₃ and brine, dried (MgSO₄), filtered, andconcentrated. The residue was purified by flash chromatography on SiO₂using 1:1 hexanes:EtOAc as eluent providing 53 mg of desired the desiredpyridyl-ether. This material was dissolved in 2 mL EtOH and 1 mL EtOAc,treated with ammonium formate (85 mg) and catalytic palladium-on-carbon(10%, 15 mg). The mixture was heated at 65° C. for 20 min, cooled toroom temperature, filtered over diatomaceous earth, washed with water,brine and dried (MgSO₄). The solvent was removed in vacuo, then theresidue was dissolved in 2 mL EtOH and 1 mL of 4 N HCl in 1,4-dioxane.The mixture was heated at 75° C. for 25 min, then concentrated in vacuo.The residue was taken up in EtOAc, and washed with saturated NaHCO₃, andbrine, and dried (MgSO₄) and concentrated. The residue was purified byreverse-phase preparative HPLC providing 2 mg of the title compound.

Assessment of Biological Properties

Inhibition of TNF Production in THP Cells

The inhibition of cytokine production can be observed by measuringinhibition of TNFα in lipopolysaccharide stimulated THP cells (forexample, see W. Prichett et al., 1995, J. Inflammation, 45, 97). Allcells and reagents were diluted in RPMI 1640 with phenol red andL-glutamine, supplemented with additional L-glutamine (total: 4 mM),penicillin and streptomycin (50 units/ml each) and fetal bovine serum(FBS, 3%) (GIBCO, all conc. final). Assay was performed under sterileconditions; only test compound preparation was nonsterile. Initial stocksolutions were made in DMSO followed by dilution into RPMI 1640 2-foldhigher than the desired final assay concentration. Confluent THP.1 cells(2×10⁶ cells/ml, final conc.; American Type Culture Company, Rockville,Md.) were added to 96 well polypropylene round bottomed culture plates(Costar 3790; sterile) containing 125 μl test compound (2 foldconcentrated) or DMSO vehicle (controls, blanks). DMSO concentration didnot exceed 0.2% final. Cell mixture was allowed to preincubate for 30min, 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS; 1μg/ml final; Siga L-2630, from E.coli serotype 0111.B4; stored as 1mg/ml stock in endotoxin screened distilled H₂O at −80° C.). Blanks(unstimulated) received H₂O vehicle; final incubation volume was 250 μl.Overnight incubation (18-24 hr) proceeded as described above. Assay wasterminated by centrifuging plates 5 min, room temperature, 1600 rpm(400×g); supernatants were transferred to clean 96 well plates andstored −80° C. until analyzed for human TNFα by a commercially availableELISA kit (Biosource #KHC3015, Camarillo, Calif.). Data was analyzed bynon-linear regression (Hill equation) to generate a dose response curveusing SAS Software System (SAS institute, Inc., Cary, N.C.). Thecalculated IC50 value is the concentration of the test compound thatcaused a 50% decrease in the maximal TNFα production.

Preferred compounds including those from the synthetic examples abovewere evaluated and had IC₅₀<10 μM in this assay.

Inhibition of Other Cytokines

By similar methods using peripheral blood monocytic cells, appropriatestimuli, and commercially available ELISA kits (or other method ofdetection such as radioimmunoassay), for a particular cytokine,inhibition of IL-1β, GM-CSF, IL-6 and IL-8 can be demonstrated (forexample, see J. C. Lee et al., 1988, Int. J. Immunopharmacol., 10, 835).

We claim:
 1. A compound of the formula (I):

wherein: ring A is: fused saturated or unsaturated ring containing 3-5carbon atoms wherein ring A or the phenyl ring to which it is fused isoptionally substituted by one or more C₁₋₆ branched or unbranched alkyl,acetyl, benzoyl, naphthoyl, C₁₋₆ branched or unbranched alkoxy, halogen,methoxycarbonyl, phenylsulfonyl, hydroxy, amino, mono- or di-(C₁₋₄alkyl)amino, mono- or di-(C₁₋₄ alkyl)amino-S(O)_(m), cyano, nitro orH₂NSO₂; G is a 5-membered heteroaryl ring; wherein G is optionallysubstituted by one or more R₁, R₂ or R₃; Q is a carbocyclic ring chosenfrom naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl,benzocycloheptanyl, benzocycloheptenyl, indanyl and indenyl; a ringsystem chosen from benzoxazinyl, benzimidazolyl, benzothiazolyl,benzooxazolyl, benzofuranyl, benzopyranyl, benzodioxolyl, quinaldinyl,quinazolinyl, quinoxalinyl, isoquinolinyl, quinolinyl, indolyl,isoindolyl, indolinyl, purinyl, tetrahydroquinolinyl, indazolyl,imidazo-pyridinyl, pyrazolo-pyridinyl, pyrazolo-pyrimidinyl,pyrrolo-pyrimidinyl, pyrrolo-pyridinyl, pyrido-pyrazinyl,pyrido-pyrimidinyl, pyrido-oxazinyl, pyrido-thiazinyl, pyrido-oxazolyl,pyrido-thioxazolyl, pyrimido-pyrimidine, pteridinyl, cinnolinyl andnaphthyridinyl; wherein each Q is optionally substituted with one tothree Y, each Y is independently chosen from L-NR₅R₆ wherein L is abond, —(CH₂)₁₋₅— or >C(O), hydrogen, oxo, C₁₋₅ alkyl branched orunbranched, C₁₋₃ alkyl(OH), C₂₋₅ alkenyl, C₁₋₃ acyl, heterocyclylC₀₋₃alkyl wherein the heterocyclyl is chosen from morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl, tetrahydropyranyl and tetrahydrofuryl,heteroarylC₀₋₃ alkyl wherein the heteroaryl is chosen from pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl,isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzopyrazolyl,benzothiofuranyl, quinoxalinyl, quinazolinyl and indazolyl andphenylC₀₋₃ alkyl or naphthylC₀₋₃ alkyl, wherein each Y is optionallysubstituted by one to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄acyl, C₁₋₅ alkoxycarbonyl, —NR₅R₆ or NR₅R₆—C(O)—; each R₅ or R₆ isindependently: hydrogen, phenylC₀₋₃ alkyl, naphthylC₀₋₃ alkyl, C₃₋₇cycloalkylC₀₋₃ alkyl, heterocyclylC₀₋₃ alkyl or heterocyclylcarbonylwherein the heterocyclyl is as hereinabove described for Y,heteroarylC₀₋₃ alkyl or heteroarylcarbonyl wherein the heteroaryl is ashereinabove described for Y, C₁₋₃ acyl, benzoyl, naphthoyl or C₁₋₆branched or unbranched alkyl, each R₅ or R₆ is optionally substituted byC₁₋₅ alkoxy, hydroxy, mono- or di-C₁₋₃alkylaminocarbonyl, mono or diC₁₋₃alkyl amino, mono or diC₁₋₃ alkylsulfonylamino or C₁₋₃ alkylsulfonyl;each R₁ is independently: C₁₋₁₀ alkyl branched or unbranched, whereinone or more C atoms are optionally independently replaced by O, N orS(O)_(m), and wherein said C₁₋₁₀ alkyl is optionally substituted withone to three C₃₋₁₀ cycloalkyl, hydroxy, oxo, phenyl, naphthyl orhalogen; or R₁ is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy or cycloheptyloxy each optionally substituted with one tothree C₁₋₃ alkyl groups, nitrile, hydroxyC₁₋₃alkyl, phenyl or naphthyl;phenyloxy or benzyloxy each optionally substituted with one to threeC₁₋₃ alkyl groups, nitrile, hydroxyC₁₋₃alkyl, phenyl or naphthyl;cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each beingoptionally substituted with one to three C₁₋₃ alkyl, nitrile,hydroxyC₁₋₃alkyl, phenyl or naphthyl; C₃₋₁₀ branched or unbrancedalkenyl each being optionally substituted with one to three C₁₋₅branched or unbranched alkyl, phenyl or naphthyl; cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,bicyclohexenyl or bicycloheptenyl, wherein each optionally substitutedwith one to three C₁₋₃ alkyl groups; oxo, nitrile, halogen; or C₃₋₆alkynyl branched or unbranched carbon chain wherein one or moremethylene groups are optionally replaced by O, N or S(O)_(m) and whereinsaid alkynyl group is optionally independently substituted with one totwo oxo groups, hydroxy, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, C₁₋₄alkyl optionally substituted by one or more halogen atoms, nitrile,morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl,tetrazolyl or mono- or di(C₁₋₃alkyl)amino; each R₂ is independently: aC₁₋₆ branched or unbranched alkyl optionally halogenated, C₁₋₆acyl,benzoyl, naphthoyl, C₁₋₄ branched or unbranched alkoxy optionallyhalogenated, halogen, methoxycarbonyl, C₁₋₄ alkyl-S(O)_(m) branched orunbranched or phenyl-S(O)_(m); each R₃ is independently C₁₋₆ branched orunbranched alkyl, phenylC₀₋₆ alkyl, naphthylC₀₋₆ alkyl, heteroarylC₀₋₆alkyl or heterocyclyl C₀₋₆ alkyl each optionally substituted with one tothree C₁₋₃ alkyl groups, nitrile, hydroxyC₁₋₃alkyl or aryl; each m isindependently 0, 1 or 2; and X is O or S; or the pharmaceuticallyacceptable salts thereof; with the proviso that the following compoundsare excluded:1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(1-morpholin-4-yl-indan-5-yl)-naphthalen-1-yl]-ureaand1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6-yl)naphthalen-1-yl]-urea.2. The compound according to claim 1 wherein: ring A and the phenyl ringto which it is fused form:


3. The compound according to claim 2 wherein: G is pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl; wherein G isoptionally substituted by one to three R₁, R₂ or R₃; ring A and thephenyl ring to which it is fused form:

Q is a ring system chosen from benzimidazolyl, benzothiazolyl,benzooxazolyl, benzisoxazolyl, benzofuranyl, benzodioxolyl, indolyl,isoindolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, purinyl,indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzopyranyl,benzoxazinyl, pyrido[2,3-b]oxazinyl, pyrido[2,3-b]pyrazinyl,pyrido[2,3-b]thiazinyl, pyrrolo[3,2-c]pyridinyl andpyrazolo[3,4-d]pyrimidinyl; wherein each Q is optionally substitutedwith one to three Y, R₁ is C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy each branched orunbranched and optionally substituted with one to three C₃₋₁₀cycloalkyl, hydroxy, oxo, phenyl, naphthyl or halogen, or R₁ iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each optionallysubstituted with one to three C₁₋₃ alkyl, nitrile, hydroxyC₁₋₃alkylphenyl or naphthyl; R₃ is C₁₋₆ branched or unbranched alkyl, phenyl,naphthyl, benzyl, phenethyl, heteroarylC₀₋₆ alkyl wherein the heteroarylis chosen from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl,triazolyl, tetrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzopyrazolyl, benzothiofuranyl, quinoxalinyl, quinazolinyl andindazolyl or heterocyclylC₀₋₆ alkyl wherein the heterocyclyl is chosenfrom morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl andtetrahydrofuryl, each optionally substituted with one to three C₁₋₃alkyl; and X is O.
 4. The compound according to claim 3 wherein: G ispyrrolyl, imidazolyl or pyrazolyl, wherein G is optionally substitutedby one to three R₁, R₂ or R₃; each Y is independently chosen fromL-NR₅R₆ wherein L is a bond, —(CH₂)₁₋₅— or >C(O), hydrogen, oxo, C₁₋₅alkyl branched or unbranched, C₁₋₃ alkyl(OH), C₂₋₅ alkenyl, C₁₋₃ acyl,heterocyclylC₀₋₃ alkyl wherein the heterocyclyl is chosen frommorpholinyl, piperazinyl, and pyrrolidinyl, heteroarylC₀₋₃ alkyl whereinthe heteroaryl is chosen from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, andoxazolyl, phenyl, naphthyl, benzyl and phenethyl, wherein each Y isoptionally substituted by one to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃alkoxy, C₁₋₄ acyl, C₁₋₅ alkoxycarbonyl or —NR₅R₆; each R₅ or R₆ isindependently: hydrogen, phenyl, naphthyl, benzyl, phenethyl, C₃₋₇cycloalkylC₀₋₃ alkyl, heterocyclylC₀₋₃ alkyl or heterocyclylcarbonylwherein the heterocyclyl is chosen from morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, heteroarylC₀₋₃ alkyl or heteroarylcarbonyl whereinthe heteroaryl is chosen from pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl, C₁₋₃ acyl, benzoyl, naphthoyl or C₁₋₆ branched orunbranched alkyl, each R₅ or R₆ is optionally substituted by C₁₋₅alkoxy, mono or diC₁₋₃ alkyl amino, mono or diC₁₋₃ alkylsulfonylamino orC₁₋₃ alkylsulfonyl; R₁ is C₁₋₁₀ alkyl, C₁₋₉ alkoxy each branched orunbranched and optionally substituted with one to three C₃₋₁₀cycloalkyl, hydroxy, oxo, phenyl, naphthyl, fluoro, bromo or chloro; andR₃ is C₁₋₆ branched or unbranched alkyl, phenyl, naphthyl, benzyl,phenethyl, pyridinyl, morpholinyl, piperazinyl, piperidinyl orpyrrolidinyl each optionally substituted with one to three C₁₋₃ alkyl.5. The compound according to claim 4 wherein: G is pyrazolyl optionallysubstituted by one to three R₁, R₂ or R₃; Q is chosen fromimidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrido[2,3-b]oxazinyland pyrrolo[3,2-c]pyridinyl; wherein each Q is optionally substitutedwith one to three Y; each Y is independently chosen from L-NR₅R₆ whereinL is a bond, —(CH₂)₁₋₅— or >C(O), hydrogen, oxo, C₁₋₅ alkyl branched orunbranched, heterocyclylC₀₋₃ alkyl wherein the heterocyclyl is chosenfrom morpholinyl, piperazinyl, and pyrrolidinyl, pyridinylC₀₋₃ alkyl orbenzyl, wherein each Y is optionally substituted by one to threehydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl or —NR₅R₆; and each R₅or R₆ is independently: hydrogen, phenyl, benzyl, C₃₋₆ cycloalkylC₀₋₃alkyl, heterocyclylC₀₋₃ alkyl or heterocyclylcarbonyl wherein theheterocyclyl is chosen from morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, pyridinylC₀₋₃ alkyl, pyridinylcarbonyl, C₁₋₃ acyl,benzoyl or C₁₋₆ branched or unbranched alkyl, each R₅ or R₆ isoptionally substituted by C₁₋₅ alkoxy, mono or diC₁₋₃ alkyl amino, monoor diC₁₋₃ alkylsulfonylamino or C₁₋₃ alkylsulfonyl.
 6. The compoundaccording to claim 5 wherein: G is 2H-pyrazol-3-yl optionallysubstituted by one to three R₁, R₂ or R₃; Q is chosen from:

R₁ is CF₃, OCF₃, —C(CH₃)₃, —C(CH₂F)₃ or —CH₂C(CH₃)₃; and R₃ is phenyl orbenzyl each optionally substituted with one to three C₁₋₃ alkyl.
 7. Thecompound according to claim 6 wherein: G is:

Q is chosen from

Y is independently chosen from L-NR₅R₆ wherein L is a bond or—(CH₂)₁₋₃—, C₁₋₅ alkyl branched or unbranched, morpholinylC₀₋₃ alkyl orbenzyl; and each R₅ or R₆ is independently: hydrogen, phenyl, benzyl orC₃₋₆ cycloalkylC₀₋₃ alkyl.
 8. A compound of the formula (II):

wherein: ring A is: fused saturated or unsaturated ring containing 3-5carbon atoms wherein ring A or the phenyl ring to which it is fused isoptionally substituted by one or more a C₁₋₆ branched or unbranchedalkyl, acetyl, benzoyl, naphthoyl, C₁₋₆ branched or unbranched alkoxy,halogen, methoxycarbonyl, phenylsulfonyl, hydroxy, amino, mono- ordi-(C₁₋₄ alkyl)amino, mono- or di-(C₁₋₄ alkyl)amino-S(O)_(m), cyano,nitro or H₂NSO₂; G is a 6-membered monocyclic heteroaryl ring chosenfrom pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; a ring systemchosen from benzoxazinyl, benzimidazolyl, benzothiazolyl, benzooxazolyl,benzofuranyl, benzopyranyl, benzodioxolyl, quinaldinyl, quinazolinyl,quinoxalinyl, isoquinolinyl, quinolinyl, indolyl, isoindolyl, indolinyl,purinyl, indazolyl, imidazo-pyridinyl, pyrazolo-pyridinyl,pyrazolo-pyrimidinyl, pyrrolo-pyrimidinyl, pyrrolo-pyridinyl,pyrido-pyrazinyl, pyrido-pyrimidinyl, pyrido-oxazinyl, pyrido-thiazinyl,pyrido-oxazolyl, pyrido-thioxazolyl, pyrimido-pyrimidine, pteridinyl,cinnolinyl and naphthyridinyl; a 3-7 membered carbocyclic ring aromaticor nonaromatic; wherein G is optionally substituted by one or more R₁,R₂ or R₃; Q is a carbocyclic ring chosen from naphthyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl,benzocycloheptanyl, benzocycloheptenyl, indanyl and indenyl; a ringsystem chosen from benzoxazinyl, benzimidazolyl, benzothiazolyl,benzooxazolyl, benzofuranyl, benzopyranyl, benzodioxolyl, quinaldinyl,quinazolinyl, quinoxalinyl, isoquinolinyl, quinolinyl, indolyl,isoindolyl, indolinyl, purinyl, tetrahydroquinolinyl, indazolyl,imidazo-pyridinyl, pyrazolo-pyridinyl, pyrazolo-pyrimidinyl,pyrrolo-pyrimidinyl, pyrrolo-pyridinyl, pyrido-pyrazinyl,pyrido-pyrimidinyl, pyrido-oxazinyl, pyrido-thiazinyl, pyrido-oxazolyl,pyrido-thioxazolyl, pyrimido-pyrimidine, pteridinyl, cinnolinyl andnaphthyridinyl; wherein each Q is optionally substituted with one tothree Y, each Y is independently chosen from L-NR₅R₆ wherein L is abond, —(CH₂)₁₋₅— or >C(O), hydrogen, oxo, C₁₋₅ alkyl branched orunbranched, C₁₋₃ alkyl(OH), C₂₋₅ alkenyl, C₁₋₃ acyl, heterocyclylC₀₋₃alkyl wherein the heterocyclyl is chosen from morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl and tetrahydrofuryl, heteroarylC₀₋₃ alkylwherein the heteroaryl is chosen from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiofuranyl,quinoxalinyl, quinazolinyl and indazolyl phenylC₀₋₃ alkyl andnaphthylC₀₋₃ alkyl, wherein each Y is optionally substituted by one tothree hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl, C₁₋₅alkoxycarbonyl, —NR₅R₆ or NR₅R₆—C(O)—; each R₅ or R₆ is independently:hydrogen, phenylC₀₋₃ alkyl, naphthylC₀₋₃ alkyl, C₃₋₇ cycloalkylC₀₋₃alkyl, heterocyclylC₀₋₃ alkyl or heterocyclylcarbonyl wherein theheterocyclyl is as hereinabove described for Y, heteroarylC₀₋₃ alkyl orheteroarylcarbonyl wherein the heteroaryl is as hereinabove describedfor Y, C₁₋₃ acyl, benzoyl, naphthoyl or C₁₋₆ branched or unbranchedalkyl, each R₅ or R₆ is optionally substituted by C₁₋₅ alkoxy, hydroxy,mono- or di-C₁₋₃alkylaminocarbonyl, mono or diC₁₋₃ alkylamino, mono ordiC₁₋₃ alkylsulfonylamino or C₁₋₃ alkylsulfonyl; each R₁ isindependently: C₁₋₁₀ alkyl branched or unbranched, wherein one or more Catoms are optionally independently replaced by O, N or S(O)_(m), andwherein said C₁₋₁₀ alkyl is optionally substituted with one to threeC₃₋₁₀ cycloalkyl, hydroxy, oxo, phenyl, naphthyl or halogen, or R₁ isphenyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy orcycloheptyloxy each optionally substituted with one to three C₁₋₃ alkylgroups, nitrile, hydroxyC₁₋₃alkyl phenyl or naphthyl; phenyloxy orbenzyloxy each optionally substituted with one to three C₁₋₃ alkylgroups, nitrile, hydroxyC₁₋₃alkyl phenyl or naphthyl; cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl,bicyclohexanyl or bicycloheptanyl, each being optionally substitutedwith one to three C₁₋₃ alkyl, nitrile, hydroxyC₁₋₃alkyl phenyl ornaphthyl; C₃₋₁₀ branched or unbranced alkenyl each being optionallysubstituted with one to three C₁₋₅ branched or unbranched alkyl, phenylor naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, eachoptionally substituted with one to three C₁₋₃ alkyl groups; morpholinyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl ortetrahydrofuryl, oxo, nitrile, halogen; or C₃₋₆ alkynyl branched orunbranched carbon chain wherein one or more methylene groups areoptionally replaced by O, N or S(O)_(m) and wherein said alkynyl groupis optionally independently substituted with one to two oxo groups,hydroxy, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, one or more C₁₋₄alkyl optionally substituted by one or more halogen atoms, nitrile,morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl,tetrazolyl or mono- or di(C₁₋₃alkyl)amino; each R₂ is independently: aC₁₋₆ branched or unbranched alkyl optionally halogenated, C₁₋₆acyl,benzoyl, naphthoyl, C₁₋₄ branched or unbranched alkoxy optionallyhalogenated, halogen, methoxycarbonyl, C₁₋₄ alkyl-S(O)_(m) branched orunbranched or phenyl-S(O)_(m); each R₃ is independently C₁₋₆ branched orunbranched alkyl, phenylC₀₋₆ alkyl, naphthylC₀₋₆ alkyl, heteroarylC₀₋₆alkyl, heterocyclyl C₀₋₆ alkyl each optionally substituted with one tothree C₁₋₃ alkyl groups, nitrile, hydroxyC₁₋₃alkyl phenyl or naphthyl;amino wherein the nitrogen atom is optionally mono- or di-substituted byC₁₋₆ branched or unbranched alkyl, phenylC₀₋₆ alkyl, naphthylC₀₋₆ alkyl,heteroarylC₀₋₆ alkyl and heterocyclyl C₀₋₆ alkyl; J-S(O)_(m)—NR₇—wherein the nitrogen atom is covalently attached to G; or R₃ isJ-NR₇—C(O)—, wherein R₇ is hydrogen or C₁₋₃ alkyl; J is chosen from C₁₋₆branched or unbranched alkyl optionally substituted with 1 to 3 halogenatoms, phenylC₀₋₆ alkyl, naphthylC₀₋₆ alkyl, heteroarylC₀₋₆ alkyl andheterocyclyl C₀₋₆ alkyl; each m is independently 0, 1 or 2; and X is Oor S; or the pharmaceutically acceptable salts.
 9. The compoundaccording to claim 8 and wherein ring A and the phenyl ring to which itis fused form:


10. The compound according to claim 9 and wherein G is a 6-memberedmonocyclic heteroaryl ring chosen from pyridinyl, pyrimidinyl, pyrazinyland pyridazinyl; phenyl, naphthyl, indanyl, indenyl or C₃₋₇ cycloalkyl;wherein G is optionally substituted by one to three R₁, R₂ or R₃; ring Aand the phenyl ring to which it is fused form:

Q is a ring system chosen from benzimidazolyl, benzothiazolyl,benzooxazolyl, benzisoxazolyl, benzofuranyl, benzofuranyl,benzodioxolyl, indolyl, isoindolyl, imidazo[4,5-b]pyridinyl,imidazo[4,5-c]pyridinyl, purinyl, indazolyl, quinolinyl, isoquinolinyl,quinazolinyl, benzopyranyl, benzoxazinyl, pyrido[2,3-b]oxazinyl,pyrido[2,3-b]pyrazinyl, pyrido[2,3-b]thiazinyl, pyrrolo[3,2-c]pyridinyland pyrazolo[3,4-d]pyrimidinyl; wherein each Q is optionally substitutedwith one to three Y, R₁ is C₁₋₁₀ alkyl, C₁₋₉ alkoxy each branched orunbranched and optionally substituted with one to three C₃₋₁₀cycloalkyl, hydroxy, oxo, phenyl, naphthyl or halogen, morpholinyl,piperazinyl, piperidinyl, or R₁ is phenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl orbicycloheptanyl, each being optionally substituted with one to threeC₁₋₃ alkyl, nitrile, hydroxyC₁₋₃alkyl phenyl or naphthyl; R₂ is halogen,C₁₋₆ branched or unbranched alkyl or C₁₋₄ branched or unbranched alkoxyeach optionally halogenated; R₃ is J-S(O)_(m)—NR₇— wherein the nitrogenatom is covalently attached to G and wherein J is chosen from a C₁₋₆branched or unbranched alkyl optionally substituted with 1 to 3 halogenatoms, phenylC₀₋₆ alkyl, naphthylC₀₋₆ alkyl, heteroarylC₀₋₆ alkyl andheterocyclyl C₀₋₆ alkyl; and X is O.
 11. The compound according to claim10 and wherein G is pyridinyl, phenyl, naphthyl, indanyl, indenyl orC₃₋₇ cycloalkyl; wherein G is optionally substituted by one to three R₁,R₂ or R₃; wherein each Y is independently chosen from L-NR₅R₆ wherein Lis a bond or —(CH₂)₁₋₅—; hydrogen, oxo, C₁₋₅ alkyl branched orunbranched, C₁₋₃ acyl, heterocyclylC₀₋₃ alkyl wherein the heterocyclylis chosen from morpholinyl, piperazinyl, and pyrrolidinyl,heteroarylC₀₋₃ alkyl wherein the heteroaryl is chosen from pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,isoxazolyl, thiazolyl and oxazolyl, phenyl, naphthyl, benzyl andphenethyl, wherein each Y is optionally substituted by one to threehydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl, C₁₋₅ alkoxycarbonyl or—NR₅R₆; each R₅ or R₆ is independently: hydrogen, phenyl, naphthyl,benzyl, phenethyl, C₃₋₇ cycloalkylC₀₋₃ alkyl, heterocyclylC₀₋₃ alkyl orheterocyclylcarbonyl wherein the heterocyclyl is chosen frommorpholinyl, tetrahydrofuranyl and tetrahydropyranyl, heteroarylC₀₋₃alkyl or heteroarylcarbonyl wherein the heteroaryl is chosen frompyridinyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, C₁₋₃ acyl,benzoyl, naphthoyl or C₁₋₆ branched or unbranched alkyl, each R₅ or R₆is optionally substituted by C₁₋₅ alkoxy, mono or diC₁₋₃ alkyl amino,mono or diC₁₋₃ alkylsulfonylamino or C₁₋₃ alkylsulfonyl; R₁ is C₁₋₁₀alkyl, C₁₋₉ alkoxy each branched or unbranched and optionallysubstituted with one to three C₃₋₁₀ cycloalkyl, hydroxy, oxo, phenyl,naphthyl, fluoro, bromo or chloro or R₁ is morpholinyl or phenyl; and R₃is J-S(O)_(m)—NR₇— wherein the nitrogen atom is covalently attached to Gand wherein J is chosen from a C₁₋₆ branched or unbranched alkyloptionally substituted with 1 to 3 halogen atoms phenylC₀₋₆ alkyl, andnaphthylC₀₋₆ alkyl.
 12. The compound according to claim 11 and wherein Gis pyridinyl, phenyl, cyclopropyl or naphthyl each optionallysubstituted by one to three R₁, R₂ or R₃; Q is chosen fromimidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrido[2,3-b]oxazinyl,pyrido[2,3-b]pyrazinyl, pyrido[2,3-b]thiazinyl,pyrazolo[3,4-d]pyrimidinyl, isoquinolinyl, purinyl andpyrrolo[3,2-c]pyridinyl; wherein each Q is optionally substituted withone to three Y, wherein each Y is independently chosen from L-NR₅R₆wherein L is a bond or —(CH₂)₁₋₅—, hydrogen, oxo, C₁₋₅ alkyl branched orunbranched, heterocyclylC₀₋₃ alkyl wherein the heterocyclyl is chosenfrom morpholinyl, piperazinyl, and pyrrolidinyl, pyridinylC₀₋₃ alkyl orbenzyl, wherein each Y is optionally substituted by one to threehydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₄ acyl or —NR₅R₆; each R₅ orR₆ is independently: hydrogen, phenyl, benzyl, C₃₋₆ cycloalkylC₀₋₃alkyl, heterocyclylC₀₋₃ alkyl or heterocyclylcarbonyl wherein theheterocyclyl is chosen from morpholinyl, tetrahydrofuranyl andtetrahydropyranyl, pyridinylC₀₋₃ alkyl, pyridinylcarbonyl, C₁₋₃ acyl,benzoyl or C₁₋₆ branched or unbranched alkyl optionally substituted byC₁₋₅ alkoxy, mono or diC₁₋₃ alkyl amino, mono or diC₁₋₃alkylsulfonylamino or C₁₋₃ alkylsulfonyl; R₇ is hydrogen; and J is C₁₋₆branched or unbranched alkyl optionally substituted with 1 to 3 halogenatoms.
 13. The compound according to claim 12 and wherein Q is chosenfrom:

R₁ is morpholinyl, phenyl, CF₃, OCF₃, —C(CH₃)₃, —C(CH₂F)₃ or—CH₂C(CH₃)₃; R₂ is chloro, bromo, fluoro, C₁₋₄ branched or unbranchedalkoxy, CF₃ or OCF₃; and J is C₁₋₃ alkyl optionally substituted with 1to 3 halogen atoms.
 14. The compound according to claim 13 and wherein Gis:


15. The compound according to claim 14 and wherein G is:

Y is independently chosen from L-NR₅R₆ wherein L is a bond or—(CH₂)₁₋₃—, C₁₋₅ alkyl branched or unbranched, morpholinylC₀₋₃ alkyl orbenzyl; and each R₅ or R₆ is independently: hydrogen, phenyl, benzyl orC₃₋₆ cycloalkylC₀₋₃ alkyl.
 16. A compound chosen from:1-[4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea;1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-pyrrolo[3,2-c]pyridin-1-yl-naphthalen-1-yl)-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(3H-imidazol[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydro-4-lambda-4-pyrido[2,3-b][1,4]thiazin-7-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,4,4-trioxo-1,2,3,4-tetrahydro-4-lambda-6-pyrido[2,3-b][1,4]thiazin-7-yl)-naphthalen-1-yl]-urea;N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;N-(5-tert-Butyl-2-methoxy-3-{3-[4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;N-(3-{3-[4-(3-Benzyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-ureido}-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide;N-{5-tert-Butyl-2-methoxy-3-[3-(4-pyrrolo[3,2-c]pyridin-1-yl-naphthalen-1-yl)-ureido]-phenyl}-methanesulfonamide;1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-pyrrolo[3,2-c]pyridin-1-yl-naphthalen-1-yl)-urea;N-{5-tert-Butyl-3-[3-(4-imidazo[4,5-c]pyridin-3-yl-naphthalen-1-yl)-ureido]-2-methoxy-phenyl}-methanesulfonamide;N-{5-tert-Butyl-3-[3-(4-imidazo[4,5-c]pyridin-1-yl-naphthalen-1-yl)-ureido]-2-methoxy-phenyl}-methanesulfonamide1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[3-(2-morpholin-4-yl-ethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[3-(2-dimethylamino-ethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(3-pyridin-2-ylmethyl-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;1-[4-(1-Benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;1-[4-(2-Amino-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;N-(6-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-acetamide;N-(6-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-benzamide;N-(6-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-nicotinamide;N-(6-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-methanesulfonamide;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(3-methanesulfonyl-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-diethylaminomethyl-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-pyrrolidin-1-ylmethyl-3H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-(4-methyl-piperazin-1-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,3-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl)-naphthalen-1-yl]-urea;1-[4-(3-Benzyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-oxo-3-pyridin-2-ylmethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[3-(3,4-dimethoxy-benzyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[3-(2-dimethylamino-ethyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-isoquinolin-5-yl-naphthalen-1-yl)-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-purin-9-yl-naphthalen-1-yl)-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-purin-7-yl-naphthalen-1-yl)-urea;1-[4-(6-Amino-purin-9-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-methylamino-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-dimethylamino-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-cyclopropylamino-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(cyclopropylmethyl-amino)-purin-9-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxy-ethylamino)-purin-9-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-dimethylamino-ethylamino)-purin-9-yl]-naphthalen-1-yl}-urea;1-[4-(6-Benzylamino-purin-9-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(pyridin-2-ylmethyl)-amino]-purin-9-yl}-naphthalen-1-yl)-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxy-1-methyl-ethylamino)-purin-9-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-phenyl-ethylamino)-purin-9-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-cyclopentylamino-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-isopropylamino-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-cyclohexylamino-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-furan-3-ylamino)-purin-9-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-pyrrolidin-1-yl-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-yl-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-yl)-purin-9-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-dimethylamino-ethyl)-methyl-amino]-purin-9-yl}-naphthalen-1-yl)-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-morpholin-4-yl-ethylamino)-purin-9-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-ethylamino-2-methyl-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[2-methyl-6-(2-morpholin-4-yl-ethylamino)-purin-9-yl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-cyclopropylamino-2-methyl-purin-9-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-naphthalen-1-yl]-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2,6-dioxo-1,2,3,6-tetrahydro-purin-9-yl)-naphthalen-1-yl]-urea and1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-pyrazolo[3,4-d]pyrimidin-1-yl-naphthalen-1-yl)-urea or the pharmaceutically acceptable salts.


17. A pharmaceutical composition comprising a pharmaceutically effectiveamount of a compound according to claims 1, 8 or 16 and one or morepharmaceutically acceptable carriers.
 18. A process of making a compoundaccording to claim 1:

wherein G, X, A and Q of the formula I or II are described in claim 1,comprising: reacting an arylamine of formula III with an alkyl or arylchloroformate, in a suitable solvent, optionally in the presence of asuitable base, at a temperature between 0-85° C. for 2-24 h providingcarbamate VI; reacting the carbamate and arylamine V in a non-protic,anhydrous solvent between 0-110° C. for 2-24 h, providing the product offormula I or II; wherein each aryl moiety recited hereinabove is phenylor naphthyl.
 19. A method of treating a disease or condition selectedfrom Behcet's disease, ankylosing spondylitis, rheumatoid arthritis,inflammatory bowel disease, septic shock, osteoarthritis, Crohn'sdisease, ulcerative colitis, multiple sclerosis, Guillain-Barresyndrome, psoriasis, graft versus host disease, systemic lupuserythematosus, restenosis following percutaneous transluminal coronaryangioplasty, diabetes, toxic shock syndrome, Alzheimer's disease, acuteand chronic pain, contact dermatitis, atherosclerosis,glomerulonephritis, reperfusion injury, sepsis, bone resorptiondiseases, chronic obstructive pulmonary disease, asthma, stroke,myocardial infarction, thermal injury, adult respiratory distresssyndrome (ARDS), multiple organ injury secondary to trauma, dermatoseswith acute inflammatory components, acute purulent meningitis,necrotizing enterocolitis comprising administering to a patient apharmaceutically effective amount of a compound according to claims 1, 8or
 16. 20. The method according to claim 19 wherein the disease isselected from rheumatoid arthritis, osteoarthritis, Crohn's disease,psoriasis, ulcerative colitis, osteoporosis, chronic obstructivepulmonary disease and restenosis following percutaneous transluminalcoronary angioplasty.